Aminopyrimidinyl compounds

ABSTRACT

A compound compound having the structure: 
                         
or a pharmaceutically acceptable salt thereof, wherein X is N or CR, where R is hydrogen, deuterium, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 3 -C 6  cycloalkyl, aryl, heteroaryl, aryl(C 1 -C 6  alkyl), CN, amino, alkylamino, dialkylamino, CF 3 , or hydroxyl; A is selected from the group consisting of a bond, C═O, —SO 2 —, —(C═O)NR 0 —, and —(CR a R b ) q —, where R 0  is H or C 1 -C 4  alkyl, and R a  and R b  are independently hydrogen, deuterium, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, aryl, aryl(C 1 -C 6  alkyl), heteroaryl, (C 1 -C 6  alkyl)heteroaryl, etc.; A′ is selected from the group consisting of a bond, C═O, —SO 2 —, —(C═O)NR 0 ′, —NR 0 ′(C═O)—, and —(CR a ′R b ′) q —, where R 0 ′ is H or C 1 -C 4  alkyl, and R a ′ and R b ′ are independently hydrogen, deuterium, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, aryl, aryl(C 1 -C 6  alkyl), heteroaryl, (C 1 -C 6  alkyl)heteroaryl, heteroaryl(C 1 -C 6  alkyl), and heterocyclic(C 1 -C 6  alkyl); Z is —(CH 2 ) h — or a bond, where one or more methylene units are optionally substituted by one or more C 1 -C 3  alkyl, CN, OH, methoxy, or halo, and where said alkyl may be substituted by one or more fluorine atoms; R 1  and R 1 ′ are independently selected from the group consisting of hydrogen, deuterium, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, aryl, heteroaryl, aryl(C 1 -C 6  alkyl), CN, etc., wherein said alkyl, aryl, cycloalkyl, heterocyclic, or heteroaryl is further optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6  alkyl, halo, CN, C 1 -C 4  alkylamino, C 3 -C 6  cycloalkyl, etc.; R 2  is selected from the group consisting of hydrogen, deuterium, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, halo, and cyano, where said alkyl may be substituted by one or more fluorine atoms; R 3  is selected from the group consisting of hydrogen, deuterium, and amino; R 4  is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6  alkyl, heterocycloalkyl, halo, C 3 -C 6  cycloalkyl, etc., where said alkyl, cycloalkyl, alkoxy, or heterocycloalkyl may be substituted by one or more C 1 -C 6  alkyl, halo, CN, OH, alkoxy, amino, —CO 2 H, —(CO)NH 2 , —(CO)NH(C 1 -C 6  alkyl), or —(CO)N(C 1 -C 6  alkyl) 2 , and where said alkyl may be further substituted by one or more fluorine atoms; R 5  is independently selected from the group consisting of hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, and hydroxyl; h is 1, 2 or 3; j and k are independently 0, 1, 2, or 3; m and n are independently 0, 1 or 2; and, q is 0, 1 or 2. Also provided are methods of treatment as Janus Kinase inhibitors and pharmaceutical compositions containing the compounds of the invention and combinations with other therapeutic agents.

This application is a continuation of Ser. No. 16/580,667, filed Sep.24, 2019, which is a division of Ser. No. 15/585,626, filed May 3, 2017,which was a continuation of the prior co-pending application Ser. No.14/829,753, filed Aug. 19, 2015, which claimed the benefit under 35U.S.C. §119(e) of Serial No. 62/039,969, filed Aug. 21, 2014.

FIELD OF THE INVENTION

The present invention provides pharmaceutically active amino pyrimidinylcompounds and analogues. Such compounds are useful for inhibiting JanusKinase (JAK). This invention also is directed to compositions comprisingmethods for making such compounds, and methods for treating andpreventing conditions mediated by JAK.

BACKGROUND OF THE INVENTION

Protein kinases are families of enzymes that catalyze thephosphorylation of specific residues in proteins, broadly classifiedinto tyrosine and serine/threonine kinases. Inappropriate kinaseactivity, arising from mutation, over-expression, or inappropriateregulation, dys-regulation or de-regulation, as well as over- orunder-production of growth factors or cytokines has been implicated inmany diseases, including but not limited to cancer, cardiovasculardiseases, allergies, asthma and other respiratory diseases, autoimmunediseases, inflammatory diseases, bone diseases, metabolic disorders, andneurological and neurodegenerative disorders such as Alzheimer'sdisease. Inappropriate kinase activity triggers a variety of biologicalcellular responses relating to cell growth, cell differentiation, cellfunction, survival, apoptosis, and cell mobility implicated in theaforementioned and related diseases.

Thus, protein kinases have emerged as an important class of enzymes astargets for therapeutic intervention. In particular, the JAK family ofcellular protein tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) play acentral role in cytokine signaling (Kisseleva et al., Gene, 2002, 285,1; Yamaoka et al. Genome Biology 2004, 5, 253)). Upon binding to theirreceptors, cytokines activate JAK which then phosphorylate the cytokinereceptor, thereby creating docking sites for signaling molecules,notably, members of the signal transducer and activator of transcription(STAT) family that ultimately lead to gene expression. Numerouscytokines are known to activate the JAK family. These cytokines include,the interferon (IFN) family (IFN-alpha, IFN-beta, IFN-omega, Limitin,IFN-gamma, IL-10, IL-19, IL-20, IL-22), the gp130 family (IL-6, IL-11,OSM, LIF, CNTF, NNT-1/BSF-3, G-CSF, CT-1, Leptin, IL-12, IL-23), gamma Cfamily (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), IL-3 family(IL-3, IL-5, GM-CSF), single chain family (EPO, GH, PRL, TPO), receptortyrosine kinases (EGF, PDGF, CSF-1, HGF), and G-protein coupledreceptors (AT1).

There remains a need for new compounds that effectively and selectivelyinhibit specific JAK enzymes: TYK2 and JAK1 in particular. TYK2 is a JAKkinase family member, and is important in the signaling of the type Iinterferons (IFNa, INFb) IL-6, IL-10, IL-12 and IL-23 (Liang, Y. et al.,Expert Opinion on Therapeutic Targets, 18, 5, 571-580 (2014)). As such,TYK2 signals with other members of the JAK kinase family in thefollowing combinations: TYK2/JAK1, TYK2/JAK2, TYK2/JAK1/JAK2. TYK2 hasbeen shown to be important in the differentiation and function ofmultiple cell types important in inflammatory disease and autoimmunedisease including natural killer cells, B cells, and T helper celltypes. Aberrant TYK2 expression is associated with multiple autoimmuneor inflammatory conditions. JAK1 is a member of the Janus family ofprotein kinases composed of JAK1, JAK2, JAK3 and TYK2. JAK1 is expressedto various levels in all tissues. Many cytokine receptors signal throughpairs of JAK kinases in the following combinations: JAK1/JAK2,JAK1/JAK3, JAK1/TYK2, JAK2/TYK2 or JAK2/JAK2. JAK1 is the most broadlypaired JAK kinase in this context and is required for signaling byγ-common (IL-2Rγ) cytokine receptors, IL-6 receptor family, Type I, IIand III receptor families and IL-10 receptor family. Animal studies haveshown that JAK1 is required for the development, function andhomeostasis of the immune system. Modulation of immune activity throughinhibition of JAK1 kinase activity can prove useful in the treatment ofvarious immune disorders (Murray, P. J., J. Immunol., 178, 2623-2629(2007); Kisseleva, T., et al., Gene, 285, 1-24 (2002); O'Shea, J. J., etal., Cell, 109 (suppl.). S121-S131 (2002)) while avoiding JAK2 dependenterythropoietin (EPO) and thrombopoietin (TPO) signaling (Neubauer H., etal., Cell, 93(3), 397-409 (1998); Parganas E., et al., Cell, 93(3),385-95 (1998)).

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I having thestructure:

or a pharmaceutically acceptable salt thereof, wherein X is N or CR,where R is hydrogen, deuterium, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₃-C₆cycloalkyl, aryl, heteroaryl, aryl(C₁-C₆ alkyl), CN, amino, alkylamino,dialkylamino, CF₃, or hydroxyl;

A is selected from the group consisting of a bond, C═O, —SO₂—,—(C═O)NR₀—, and —(CR_(a)R_(b))_(q)—, where R₀ is H or C₁-C₄ alkyl, andR_(a) and R_(b) are independently hydrogen, deuterium, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, aryl, aryl(C₁-C₆ alkyl), heteroaryl, (C₁-C₆alkyl)heteroaryl, heteroaryl(C₁-C₆ alkyl), and heterocyclic(C₁-C₆alkyl);

A′ is selected from the group consisting of a bond, C═O, —SO₂—,—(C═O)NR₀′, —NR₀′(C═O)—, and —(CR_(a)′R_(b)′)_(q)—, where R₀′ is H orC₁-C₄ alkyl, and R_(a)′ and R_(b)′ are independently hydrogen,deuterium, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, aryl, aryl(C₁-C₆ alkyl),heteroaryl, (C₁-C₆ alkyl)heteroaryl, heteroaryl(C₁-C₆ alkyl), andheterocyclic(C₁-C₆ alkyl);

Z is —(CH₂)_(n)— or a bond, where one or more methylene units areoptionally substituted by one or more C₁-C₃ alkyl, CN, OH, methoxy, orhalo, and where said alkyl may be substituted by one or more fluorineatoms;

R₁ and R₁′ are independently selected from the group consisting ofhydrogen, deuterium, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, aryl, heteroaryl,aryl(C₁-C₆ alkyl), CN, amino, alkylamino, dialkylamino, fluoroalkyl,alkoxy, heteroaryl(C₁-C₆ alkyl), heterocyclic and heterocyclic(C₁-C₆alkyl), wherein said alkyl, aryl, cycloalkyl, heterocyclic, orheteroaryl is further optionally substituted with one or moresubstituents selected from the group consisting of C₁-C₆ alkyl, halo,CN, hydroxy, methoxy, amino, C₁-C₄ alkyl amino, di(C₁-C₄ alkyl)amino,CF₃, —SO₂—(C₁-C₆ alkyl), and C₃-C₆ cycloalkyl;

R₂ is selected from the group consisting of hydrogen, deuterium, C₁-C₆alkyl, C₃-C₆ cycloalkyl, halo, and cyano, where said alkyl may besubstituted by one or more fluorine atoms;

R₃ is selected from the group consisting of hydrogen, deuterium, andamino;

R₄ is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroarylwherein said aryl or heteroaryl is optionally substituted with one ormore substituents selected from the group consisting of C₁-C₆ alkyl,heterocycloalkyl, halo, CN, hydroxy, —CO₂H, C₁-C₆ alkoxy, amino,—N(C₁-C₆ alkyl)(CO)(C₁-C₆ alkyl), —NH(CO)(C₁-C₆ alkyl), —(CO)NH₂,—(CO)NH(C₁-C₆ alkyl), —(CO)N(C₁-C₆ alkyl)₂, —(C₁-C₆ alkyl)amino,—N(C₁-C₆ alkyl)₂, —SO₂—(C₁-C₆ alkyl), —(SO)NH₂, and C₃-C₆ cycloalkyl,where said alkyl, cycloalkyl, alkoxy, or heterocycloalkyl may besubstituted by one or more C₁-C₆ alkyl, halo, CN, OH, alkoxy, amino,—CO₂H, —(CO)NH₂, —(CO)NH(C₁-C₆ alkyl), or —(CO)N(C₁-C₆ alkyl)₂, andwhere said alkyl may be further substituted by one or more fluorineatoms;

R₅ is independently selected from the group consisting of hydrogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, and hydroxyl;

h is 1, 2 or 3; j and k are independently 0, 1, 2, or 3; m and n areindependently 0, 1 or 2; and, q is 0, 1 or 2.

In other aspects, the present invention also provides:

pharmaceutical compositions which comprise a pharmaceutically acceptablecarrier and a compound of formula I; methods for treating conditions ordisorders including myositis, vasculitis, pemphigus, Crohn's disease,lupus, nephritis, psoriasis, multiple sclerosis, major depressiondisorder, allergy, asthma, Sjogren's disease, dry eye syndrome,transplant rejection, cancer, inflammatory bowel disease, septic shock,cardiopulmonary dysfunction, vitiligo, alopecia, acute respiratorydisease, ankylosing spondylitis, autoimmune hepatitis, primarysclerosing cholangitis, primary biliary cirrhosis, Alzheimer's disease,or cachexia by administering to a subject in need a therapeuticallyeffective amount of a compound of formula I or a pharmaceuticallyacceptable salt thereof;

methods for treating conditions or disorders including atopicdermatitis, eczema, psoriasis, scleroderma, lupus, pruritus, otherpruritic conditions, allergic reactions including allergic dermatitis inmammal, horse allergic diseases including bite hypersensitivity, summereczema, sweet itch in horses, heaves, inflammatory airway disease,recurrent airway obstruction, airway hyper-responsiveness, and chronicobstruction pulmonary disease by administering to a mammal in need atherapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof; and, methods for thepreparation of compounds of the present invention.

The present invention will be further understood from the followingdescription given by way of example only. The present invention isdirected to a class of amino pyrimidine derivatives. In particular, thepresent invention is directed to amino pyrimidine compounds useful asinhibitors of JAK, and particularly TYK2 and JAK1. While the presentinvention is not so limited, an appreciation of various aspects of theinvention will be gained through the following discussion and theexamples.

The term “alkyl”, alone or in combination, means an acyclic, saturatedhydrocarbon group of the formula C_(n)H_(2n+1) which may be linear orbranched. Examples of such groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyland hexyl. Unless otherwise specified, an alkyl group comprises from 1to 6 carbon atoms. The carbon atom content of alkyl and various otherhydrocarbon-containing moieties is indicated by a prefix designating alower and upper number of carbon atoms in the moiety, that is, theprefix C_(i)-C_(j) indicates a moiety of the integer “i” to the integer“j” carbon atoms, inclusive. Thus, for example, C₁-C₆ alkyl refers toalkyl of one to six carbon atoms, inclusive.

The term “hydroxy,” as used herein, means an OH group. The term“heterocyclic” refers to a saturated or partially saturated (i.e., nonaromatic) heterocycle which contains five to ten ring atoms where one ormore, preferably, one, two or three ring atoms, are heteratom(s)selected from N, O and S, the remaining being carbon, and which may beattached via a ring nitrogen atom or a ring carbon atom. Equally, whensubstituted, the substituent may be located on a ring nitrogen atom (ifthe substituent is joined through a carbon atom) or a ring carbon atom(in all cases). Specific examples include oxiranyl, aziridinyl,oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, piperazinyl,azepanyl, oxepanyl, oxazepanyl and diazepinyl.

The term “aryl” refers to an aromatic monocyclic or bicyclic hydrocarboncontaining six to ten ring carbon atoms which may be attached via one ofthe ring carbon atoms. Equally, when substituted, the substituent may belocated on a ring carbon atom. Specific examples include, but are notlimited to, phenyl, toluyl, xylyl, trimethylphenyl, and naphthyl.Examples of aryl substituents include, but are not limited to, alkyl,hydroxyl, halo, nitrile, alkoxy, trifluoromethyl, carboxamido, SO₂Me,benzyl, and substituted benzyl.

The term “heteroaryl” refers to a monovalent aromatic monocyclic orbicyclic heterocycle of five to ten ring atoms where one or more,preferably, one, two or three ring atoms, are heteratom(s) selected fromN, O, and S, the remaining being carbon, and which may be attached via aring carbon atom or a ring nitrogen atom with an appropriate valency.Equally, when substituted, the substituent may be located on a ringcarbon atom or a ring nitrogen atom with an appropriate valency.Specific examples include, but are not limited to, thienyl, furanyl,pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl,pyridazinyl, pyrimidinyl and pyrazinyl. The term “cycloalkyl” means amonocyclic, saturated hydrocarbon group of the formula C_(n)H_(2n−1).Examples include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise specified, acycloalkyl group comprises from 3 to 8 carbon atoms.

The terms “halo” and “halogen” refer to fluoride (F), chloride (Cl),bromide (Br) or iodide (I).

The term “mammal” refers to human, livestock or companion animals.

The term “companion animal” or “companion animals” refers to animalskept as pets or household animal. Examples of companion animals includedogs, cats, and rodents including hamsters, guinea pigs, gerbils and thelike, rabbits, ferrets and birds.

The term “livestock” refers to animals reared or raised in anagricultural setting to make products such as food or fiber, or for itslabor. In some embodiments, livestock are suitable for consumption bymammals, for example humans. Examples of livestock animals includecattle, goats, horses, pigs, sheep, including lambs, and rabbits, aswell as birds, such as chickens, ducks and turkeys.

The term “treating” or “treatment” means an alleviation of symptomsassociated with a disease, disorder or condition, or halt of furtherprogression or worsening of those symptoms. Depending on the disease andcondition of the patient, the term “treatment” as used herein mayinclude one or more of curative, palliative and prophylactic treatment.Treatment can also include administering a pharmaceutical formulation ofthe present invention in combination with other therapies.

The term “therapeutically-effective” indicates the capability of anagent to prevent, or improve the severity of, the disorder, whileavoiding adverse side effects typically associated with alternativetherapies. The phrase “therapeutically-effective” is to be understood tobe equivalent to the phrase “effective for the treatment, prevention, oramelioration”, and both are intended to qualify the amount of each agentfor use in the combination therapy which will achieve the goal ofimprovement in the severity of cancer, cardiovascular disease, or painand inflammation and the frequency of incidence over treatment of eachagent by itself, while avoiding adverse side effects typicallyassociated with alternative therapies.

“Pharmaceutically acceptable” means suitable for use in mammals,companion animals or livestock animals.

If substituents are described as being “independently selected” from agroup, each substituent is selected independent of the other. Eachsubstituent therefore may be identical to or different from the othersubstituent(s).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is related to novel compounds which are TYK2 andJAK1 modulators useful for the treatment of diseases and conditionsassociated with dysregulation of TYK2 and JAK1. The present inventionfurther provides pharmaceutical compositions comprising such JAK enzymemodulators as well as methods of treating and/or preventing suchdiseases and conditions. Accordingly, the present invention provides acompound of formula I having the structure:

or a pharmaceutically acceptable salt thereof, wherein X is N or CR,where R is hydrogen, deuterium, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₃-C₆cycloalkyl, aryl, heteroaryl, aryl(C₁-C₆ alkyl), CN, amino, alkylamino,dialkylamino, CF₃, or hydroxyl;

A is selected from the group consisting of a bond, C═O, —SO₂—,—(C═O)NR₀—, and —(CR_(a)R_(b))_(q)—, where R₀ is H or C₁-C₄ alkyl, andR_(a) and R_(b) are independently hydrogen, deuterium, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, aryl, aryl(C₁-C₆ alkyl), heteroaryl, (C₁-C₆alkyl)heteroaryl, heteroaryl(C₁-C₆ alkyl), and heterocyclic(C₁-C₆alkyl);

A′ is selected from the group consisting of a bond, C═O, —SO₂—,—(C═O)NR₀′, —NR₀′(C═O)—, and —(CR_(a)′R_(b)′)_(q)—, where R₀′ is H orC₁-C₄ alkyl, and R_(a)′ and R_(b)′ are independently hydrogen,deuterium, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, aryl, aryl(C₁-C₆ alkyl),heteroaryl, (C₁-C₆ alkyl)heteroaryl, heteroaryl(C₁-C₆ alkyl), andheterocyclic(C₁-C₆ alkyl);

Z is —(CH₂)_(h)— or a bond, where one or more methylene units areoptionally substituted by one or more C₁-C₃ alkyl, CN, OH, methoxy, orhalo, and where said alkyl may be substituted by one or more fluorineatoms;

R₁ and R₁′ are independently selected from the group consisting ofhydrogen, deuterium, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, aryl, heteroaryl,aryl(C₁-C₆ alkyl), CN, amino, alkylamino, dialkylamino, fluoroalkyl,alkoxy, heteroaryl(C₁-C₆ alkyl), and heterocyclic(C₁-C₆ alkyl), whereinsaid alkyl, aryl, cycloalkyl, heterocyclic, or heteroaryl is furtheroptionally substituted with one or more substituents selected from thegroup consisting of C₁-C₆ alkyl, halo, CN, hydroxy, methoxy, amino,C₁-C₄ alkyl amino, di(C₁-C₄ alkyl)amino, CF₃, —SO₂—(C₁-C₆ alkyl), andC₃-C₆cycloalkyl;

R₂ is selected from the group consisting of hydrogen, deuterium, C₁-C₆alkyl, C₃-C₆cycloalkyl, halo, and cyano, where said alkyl may besubstituted by one or more fluorine atoms;

R₃ is selected from the group consisting of hydrogen, deuterium, andamino;

R₄ is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroarylwherein said aryl or heteroaryl is optionally substituted with one ormore substituents selected from the group consisting of C₁-C₆ alkyl,heterocycloalkyl, halo, CN, hydroxy, —CO₂H, C₁-C₆ alkoxy, amino,—N(C₁-C₆ alkyl)(CO)(C₁-C₆ alkyl), —NH(CO)(C₁-C₆ alkyl), —(CO)NH₂,—(CO)NH(C₁-C₆ alkyl), —(CO)N(C₁-C₆ alkyl)₂, —(C₁-C₆ alkyl)amino,—N(C₁-C₆ alkyl)₂, —SO₂—(C₁-C₆ alkyl), —(SO)NH₂, and C₃-C₆ cycloalkyl,where said alkyl, cycloalkyl, alkoxy, or heterocycloalkyl may besubstituted by one or more C₁-C₆ alkyl, halo, CN, OH, alkoxy, amino,—CO₂H, —(CO)NH₂, —(CO)NH(C₁-C₆ alkyl), or —(CO)N(C₁-C₆ alkyl)₂, andwhere said alkyl may be further substituted by one or more fluorineatoms;

R₅ is independently selected from the group consisting of hydrogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, and hydroxyl;

h is 1, 2 or 3; j and k are independently 0, 1, 2, or 3; m and n areindependently 0, 1 or 2; and, q is 0, 1 or 2.

The invention also provides a compound having the structure:

or a pharmaceutically acceptable salt thereof, wherein

X is N;

A is selected from the group consisting of a bond, C═O, —SO₂—,—(C═O)NR₀—, and —(CR_(a)R_(b))_(q)—, where R₀ is H or C₁-C₄ alkyl, andR_(a) and R_(b) are independently hydrogen, deuterium, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, aryl, aryl(C₁-C₆ alkyl), heteroaryl, (C₁-C₆alkyl)heteroaryl, heteroaryl(C₁-C₆ alkyl), and heterocyclic(C₁-C₆alkyl);

R₁ is selected from the group consisting of hydrogen, deuterium, C₁-C₄alkyl, C₃-C₆ cycloalkyl, aryl, heteroaryl, aryl(C₁-C₆ alkyl), CN, amino,alkylamino, dialkylamino, fluoroalkyl, alkoxy, heteroaryl(C₁-C₆ alkyl),and heterocyclic(C₁-C₆ alkyl), wherein said alkyl, aryl, cycloalkyl,heterocyclic, or heteroaryl is further optionally substituted with oneor more substituents selected from the group consisting of C₁-C₆ alkyl,halo, CN, hydroxy, methoxy, amino, C₁-C₄ alkyl amino, di(C₁-C₄alkyl)amino, CF₃, —SO₂—(C₁-C₆ alkyl), and C₃-C₆ cycloalkyl;

R₂ is selected from the group consisting of hydrogen, deuterium, C₁-C₆alkyl, C₃-C₆ cycloalkyl, halo, and cyano, where said alkyl may besubstituted by one or more fluorine atoms;

R₃ is selected from the group consisting of hydrogen and deuterium;

R₄ is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroarylwherein said aryl or heteroaryl is optionally substituted with one ormore substituents selected from the group consisting of C₁-C₆ alkyl,heterocycloalkyl, halo, CN, hydroxy, —CO₂H, C₁-C₆ alkoxy, amino,—N(C₁-C₆ alkyl)(CO)(C₁-C₆ alkyl), —NH(CO)(C₁-C₆ alkyl), —(CO)NH₂,—(CO)NH(C₁-C₆ alkyl), —(CO)N(C₁-C₆ alkyl)₂, —(C₁-C₆ alkyl)amino,—N(C₁-C₆ alkyl)₂, —SO₂—(C₁-C₆ alkyl), —(SO)NH₂, and C₃-C₆ cycloalkyl,where said alkyl, cycloalkyl, alkoxy, or heterocycloalkyl may besubstituted by one or more C₁-C₆ alkyl, halo, CN, OH, alkoxy, amino,—CO₂H, —(CO)NH₂, —(CO)NH(C₁-C₆ alkyl), or —(CO)N(C₁-C₆ alkyl)₂, andwhere said alkyl may be further substituted by one or more fluorineatoms;

h is 1, j is 1, 2, or 3; and, q is 0, 1 or 2.

The invention further provides a compound having the structure:

or a pharmaceutically acceptable salt thereof, wherein

X is N;

A is selected from the group consisting of a bond, C═O, —SO₂—,—(C═O)NR₀—, and —(CR_(a)R_(b))_(q)—, where R₀ is H or C₁-C₄ alkyl, andR_(a) and R_(b) are independently hydrogen, deuterium, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, aryl, aryl(C₁-C₆ alkyl), heteroaryl, (C₁-C₆alkyl)heteroaryl, heteroaryl(C₁-C₆ alkyl), and heterocyclic(C₁-C₆alkyl);

R₁ is selected from the group consisting of hydrogen, deuterium, C₁-C₄alkyl, C₃-C₆ cycloalkyl, aryl, heteroaryl, aryl(C₁-C₆ alkyl), CN, amino,alkylamino, dialkylamino, fluoroalkyl, alkoxy, heteroaryl(C₁-C₆ alkyl),and heterocyclic(C₁-C₆ alkyl), wherein said alkyl, aryl, cycloalkyl,heterocyclic, or heteroaryl is further optionally substituted with oneor more substituents selected from the group consisting of C₁-C₆ alkyl,halo, CN, hydroxy, methoxy, amino, C₁-C₄ alkyl amino, di(C₁-C₄alkyl)amino, CF₃, —SO₂—(C₁-C₆ alkyl), and C₃-C₆ cycloalkyl;

R₂ is selected from the group consisting of hydrogen, deuterium, C₁-C₆alkyl, C₃-C₆ cycloalkyl, halo, and cyano, where said alkyl may besubstituted by one or more fluorine atoms;

R₃ is selected from the group consisting of hydrogen and deuterium;

R₄ is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroarylwherein said aryl or heteroaryl is optionally substituted with one ormore substituents selected from the group consisting of C₁-C₆ alkyl,heterocycloalkyl, halo, CN, hydroxy, —CO₂H, C₁-C₆ alkoxy, amino,—N(C₁-C₆ alkyl)(CO)(C₁-C₆ alkyl), —NH(CO)(C₁-C₆ alkyl), —(CO)NH₂,—(CO)NH(C₁-C₆ alkyl), —(CO)N(C₁-C₆ alkyl)₂, —(C₁-C₆ alkyl)amino,—N(C₁-C₆ alkyl)₂, —SO₂—(C₁-C₆ alkyl), —(SO)NH₂, and C₃-C₆ cycloalkyl,where said alkyl, cycloalkyl, alkoxy, or heterocycloalkyl may besubstituted by one or more C₁-C₆ alkyl, halo, CN, OH, alkoxy, amino,—CO₂H, —(CO)NH₂, —(CO)NH(C₁-C₆ alkyl), or —(CO)N(C₁-C₆ alkyl)₂, andwhere said alkyl may be further substituted by one or more fluorineatoms;

R₅ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₁-C₆alkoxy, and hydroxyl; j is 0, 1, 2, or 3; and, q is 0, 1 or 2.

The invention also provides a compound having the structure:

or a pharmaceutically acceptable salt thereof, wherein

A′ is selected from the group consisting of a bond, C═O, —SO₂—,—(C═O)NR₀′, —NR₀′(C═O)—, and —(CR_(a)′R_(b)′)_(q)—, where R₀′ is H orC₁-C₄ alkyl, and R_(a)′ and R_(b)′ are independently hydrogen,deuterium, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, aryl, aryl(C₁-C₆ alkyl),heteroaryl, (C₁-C₆ alkyl)heteroaryl, heteroaryl(C₁-C₆ alkyl), andheterocyclic(C₁-C₆ alkyl);

R₁′ is selected from the group consisting of hydrogen, deuterium, C₁-C₄alkyl, C₃-C₆ cycloalkyl, aryl, heteroaryl, aryl(C₁-C₆ alkyl), CN, amino,alkylamino, dialkylamino, fluoroalkyl, alkoxy, heteroaryl(C₁-C₆ alkyl),and heterocyclic(C₁-C₆ alkyl), wherein said alkyl, aryl, cycloalkyl,heterocyclic, or heteroaryl is further optionally substituted with oneor more substituents selected from the group consisting of C₁-C₆ alkyl,halo, CN, hydroxy, methoxy, amino, C₁-C₄ alkyl amino, di(C₁-C₄alkyl)amino, CF₃, —SO₂—(C₁-C₆ alkyl), and C₃-C₆ cycloalkyl;

R₂ is selected from the group consisting of hydrogen, deuterium, C₁-C₆alkyl, C₃-C₆ cycloalkyl, halo, and cyano, where said alkyl may besubstituted by one or more fluorine atoms;

R₃ is selected from the group consisting of hydrogen and deuterium;

R₄ is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroarylwherein said aryl or heteroaryl is optionally substituted with one ormore substituents selected from the group consisting of C₁-C₆ alkyl,heterocycloalkyl, halo, CN, hydroxy, —CO₂H, C₁-C₆ alkoxy, amino,—N(C₁-C₆ alkyl)(CO)(C₁-C₆ alkyl), —NH(CO)(C₁-C₆ alkyl), —(CO)NH₂,—(CO)NH(C₁-C₆ alkyl), —(CO)N(C₁-C₆ alkyl)₂, —(C₁-C₆ alkyl)amino,—N(C₁-C₆ alkyl)₂, —SO₂—(C₁-C₆ alkyl), —(SO)NH₂, and C₃-C₆ cycloalkyl,where said alkyl, cycloalkyl, alkoxy, or heterocycloalkyl may besubstituted by one or more C₁-C₆ alkyl, halo, CN, OH, alkoxy, amino,—CO₂H, —(CO)NH₂, —(CO)NH(C₁-C₆ alkyl), or —(CO)N(C₁-C₆ alkyl)₂, andwhere said alkyl may be further substituted by one or more fluorineatoms;

R₇ and R₈ are independently hydrogen, C₁-C₄ alkyl, aryl, heteroaryl,(aryl)C₁-C₆ alkyl, (heteroaryl)C₁-C₆ alkyl, (heterocyclic)C₁-C₆ alkyl,(C₁-C₆ alkyl)aryl, (C₁-C₆ alkyl)heteroaryl, or (C₁-C₆alkyl)heterocyclic, wherein said alkyl is further optionally substitutedwith one or more substituents selected from the group consisting ofhalo, hydroxy, methoxy, amino, CF₃, and C₃-C₆ cycloalkyl;

k is 0, 1, 2, or 3; m and n are both 1; and, q is 0, 1 or 2.

In certain embodiments, the invention provides a compound selected fromthe group consisting of:

-   [(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-({5-fluoro-6-[(3S)-3-hydroxypyrrolidin-1-yl]pyridin-3-yl}amino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;-   (1R,5S)-N-ethyl-3-[2-(1,2-thiazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   4-{(1R,5S)-8-[(2,2-difluorocyclopropyl)methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}-N-(1H-pyrazol-4-yl)pyrimidin-2-amine;-   (1R,5S)-3-(2-{[5-chloro-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-N-ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   cyclopropyl[(1R,5S)-3-(2-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   N-(1-methyl-1H-pyrazol-4-yl)-4-{(1R,5S)-8-[1-(methylsulfonyl)azetidin-3-yl]-3,8-diazabicyclo[3.2.1]oct-3-yl}pyrimidin-2-amine;-   4-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,6-dimethylpyridine-2-carboxamide;-   5-({4-[(1R,5S)-8-{[(1R,2S)-2-fluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;-   cyclopropyl[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   3-{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}butanenitrile;-   5-({4-[(1R,5S)-8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N-ethyl-3-methylpyridine-2-carboxamide;-   3-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]butanenitrile;-   5-({4-[(1R,5S)-8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3-methylpyridine-2-carboxamide;-   (1R,5S)-N-ethyl-3-(2-{[5-fluoro-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   3-chloro-5-({4-[(1R,5S)-8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N-methylpyridine-2-carboxamide;-   (1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-N-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   (3,3-difluorocyclobutyl)[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   1-({(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methyl)cyclopropanecarbonitrile;-   3-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]butanenitrile;-   (1S,2R)-2-{[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl}cyclopropanecarbonitrile;-   (1R,2S)-2-{[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl}cyclopropanecarbonitrile;-   [(1R,2R)-2-fluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   [(1R,2R)-2-fluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone-   (1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   (1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-N-[5-(trifluoromethyl)pyridin-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   N,3-dimethyl-5-[(4-{(1R,5S)-8-[(3-methyloxetan-3-yl)methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}pyrimidin-2-yl)amino]pyridine-2-carboxamide;-   {3-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]-1-(methylsulfonyl)azetidin-3-yl}acetonitrile;-   4-({4-[8-(cyanoacetyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N-ethylbenzamide;-   (1R,5S)-N-(cyanomethyl)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   5-({4-[(1R,5S)-8-{[(1S,2R)-2-fluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;-   5-({4-[(1R,5S)-8-(cis-3-cyanocyclobutyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;-   5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3-fluoropyridine-2-carboxamide-   5-({4-[(1R,5S)-8-{[(1R)-2,2-difluorocyclopropyl]methyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;-   N,3-dimethyl-5-({4-[(1R,5S)-8-(1,2-oxazol-5-ylmethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)pyridine-2-carboxamide;-   2-[5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)pyridin-2-yl]-2-methylpropanenitrile;-   3-{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}propanenitrile;-   (1R,5S)-N-ethyl-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]methyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine;-   [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-(2-{[5-fluoro-6-(2-hydroxyethyl)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-(2-{[5-fluoro-6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   [(1R,5S)-3-(2-{[5-chloro-6-(2-hydroxyethoxy)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl][(1S)-2,2-difluorocyclopropyl]methanone;-   {3-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]oxetan-3-yl}acetonitrile;-   [(1R,5S)-3-(2-{[5-chloro-6-(2-hydroxyethyl)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl][(1S)-2,2-difluorocyclopropyl]methanone;-   2-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]pyridine-4-carbonitrile;-   3-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]cyclobutanecarbonitrile;-   2-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]-1,3-oxazole-5-carbonitrile;-   (1R,5S)-N-(2-cyanoethyl)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   N-(1-methyl-1H-pyrazol-4-yl)-4-[(1R,5S)-8-(1,2-oxazol-4-ylmethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-amine;-   4-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-6-(hydroxymethyl)-N-methylpyridine-2-carboxamide;-   (1-fluorocyclopropyl)[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   N-(1-methyl-1H-pyrazol-4-yl)-4-[(1R,5S)-8-(1,3-thiazol-2-ylmethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-amine;-   cyclopropyl{(1R,5S)-3-[2-(1,2-thiazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;-   [(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-({5-fluoro-6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridin-3-yl}amino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;-   5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]methyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;-   4-[(1R,5S)-8-{[(1R)-2,2-difluorocyclopropyl]methyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine;-   6-({4-[(1R,5S)-8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-5-fluoropyrimidin-2-yl}amino)imidazo[1,2-a]pyridine-2-carboxamide;-   5-({4-[(1R,5S)-8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-5-fluoropyrimidin-2-yl}amino)pyridine-2-sulfonamide;-   5-({4-[(1R,5S)-8-(trans-3-cyanocyclobutyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;-   1,2-oxazol-5-yl{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;-   N-(1-methyl-1H-pyrazol-4-yl)-4-[(1R,5S)-8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-amine;-   (1S,2S)-2-{[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methyl}cyclopropanecarbonitrile;-   3-({4-[(1R,5S)-8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-5-fluoropyrimidin-2-yl}amino)-N-propyl-1H-pyrazole-5-carboxamide;-   (1S,2S)-2-{[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methyl}cyclopropanecarbonitrile;-   cyclopropyl{(1R,5S)-3-[5-fluoro-2-(pyridazin-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;-   4-({4-[6-(2,2-difluoropropanoyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]-5-fluoropyrimidin-2-yl}amino)-N-ethyl-2-methylbenzamide;-   (1S,2S)-2-cyano-N-[(1S,5R,6R)-3-(2-{[6-(2-hydroxyethoxy)pyridin-3-yl]amino}-5-methylpyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   N-[(1    S,5R)-3-(5-chloro-2-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}pyrimidin-4-yl)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   (1S)-2,2-difluoro-N-[(1S,5R,6R)-3-(5-fluoro-2-{[1-(oxetan-3-yl)-1H-pyrazol-4-yl]amino}pyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   (1S)-2,2-difluoro-N-[(1    S,5S)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   N-{(1S,5R,6R)-3-[5-fluoro-2-({6-[(2S)-1-hydroxypropan-2-yl]pyridin-3-yl}amino)pyrimidin-4-yl]-6-methyl-3-azabicyclo[3.1.0]hex-1-yl}cyclopropanecarboxamide;-   5-[(4-{(1S,5R,6R)-1-[(cyclopropylcarbonyl)amino]-6-methyl-3-azabicyclo[3.1.0]hex-3-yl}-5-fluoropyrimidin-2-yl)amino]-N,3-dimethylpyridine-2-carboxamide;-   N-{(1S,5R,6R)-3-[2-({5-chloro-6-[(1R)-1-hydroxyethyl]pyridin-3-yl}amino)-5-fluoropyrimidin-4-yl]-6-methyl-3-azabicyclo[3.1.0]hex-1-yl}cyclopropanecarboxamide;-   (1R)-2,2-difluoro-N-[(1R,5S,6S)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   5-[(4-{(1R,5S,6S)-1-[(cyclopropylcarbonyl)amino]-6-methyl-3-azabicyclo[3.1.0]hex-3-yl}-5-fluoropyrimidin-2-yl)amino]-N,3-dimethylpyridine-2-carboxamide;-   N-[(1R,5S)-3-(5-chloro-2-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}pyrimidin-4-yl)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;    and,-   (1S)-2,2-difluoro-N-[(1R,5S,6S)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

or, a pharmaceutically acceptable salt thereof.

In certain other embodiments, the invention provides a compound selectedfrom the group consisting of:

-   N-ethyl-4-({5-fluoro-4-[6-(2-fluoro-2-methylpropanoyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2-yl}amino)-2-methylbenzamide;-   N-ethyl-2-methyl-4-({4-[6-(trifluoroacetyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2-yl}amino)benzamide;    and,-   4-({4-[6-(2,2-difluoropropanoyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2-yl}amino)-N-ethylbenzamide;

or, a pharmaceutically acceptable salt thereof.

In yet other embodiments, the invention provides a compound selectedfrom the group consisting of:

-   4-({4-[8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-5-fluoropyrimidin-2-yl}amino)-N-ethylbenzamide;-   N-ethyl-4-({5-fluoro-4-[8-(trifluoroacetyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-2-methylbenzamide;-   (1R,5S)-3-(2-{[5-methyl-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   (1R,5S)-N-(cyanomethyl)-3-(2-{[5-methyl-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;-   tert-butyl    3-(2-{[4-(ethylcarbamoyl)-3-methylphenyl]amino}-5-fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate;-   5-({4-[(1R,5S)-8-{[(1R,2R)-2-cyanocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;-   3-chloro-5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N-methylpyridine-2-carboxamide;-   N-(1-methyl-1H-pyrazol-4-yl)-4-[(1R,5S)-8-(1,2-thiazol-5-ylmethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-amine;-   5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3-methylpyridine-2-carboxamide;-   [(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-({6-[(2S)-1-hydroxypropan-2-yl]pyridin-3-yl}amino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;-   3-chloro-5-({4-[(1R,5S)-8-{[(1R,2R)-2-cyanocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N-methylpyridine-2-carboxamide;-   [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-(2-{[5-fluoro-6-(hydroxymethyl)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   5-[(4-{(1R,5S)-8-[(2,2-difluorocyclopropyl)carbonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}pyrimidin-2-yl)amino]-3-methylpyridine-2-carboxamide;-   5-({4-[(1R,5S)-8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;-   (1R,5S)-N-ethyl-3-(2-{[5-methyl-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   [(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-({6-[(2R)-1-hydroxypropan-2-yl]pyridin-3-yl}amino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;-   N-(1-methyl-1H-pyrazol-4-yl)-4-[(1R,5S)-8-(1,2-oxazol-5-ylmethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-amine;-   cyclopropyl{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;-   5-({4-[(1R,5S)-8-{[(1R,2R)-2-cyanocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;-   [(1R)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;    and,-   5-({4-[(1R,5S)-8-{[(1R)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;

or, a pharmaceutically acceptable salt thereof.

In other embodiments, the invention provides a compound selected fromthe group consisting of:

-   (1R)-2,2-difluoro-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   N-{(1S,5R,6R)-3-[5-fluoro-2-({6-[(2R)-1-hydroxypropan-2-yl]pyridin-3-yl}amino)pyrimidin-4-yl]-6-methyl-3-azabicyclo[3.1.0]hex-1-yl}cyclopropanecarboxamide;-   N-[(1S,5R,6R)-3-(2-{[5-chloro-6-(hydroxymethyl)pyridin-3-yl]amino}-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;    and,-   N-[(1S,5R,6R)-3-(5-fluoro-2-{[6-(2-hydroxyethyl)pyridin-3-yl]amino}pyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

or, a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides a compound which is[(1S)-2,2-difluorocyclo-propyl]{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;or, a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a compound which is[(1S)-2,2-difluorocyclo-propyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;or, a pharmaceutically acceptable salt thereof.

In yet another embodiment, the invention provides a compound which is5-({4-[(1R,5S)-8-{[(1S)2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;or, a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a compound which is(1R,5S)-N-ethyl-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;or, a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides a compound which is[(1R)-2,2-difluorocyclo-propyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;or, a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a compound which is(1S)-2,2-difluoro-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide,or, a pharmaceutically acceptable salt thereof.

In a certain other embodiment, the invention provides a compound whichis(1R,2R)-2-cyano-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamideor, a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides a compound which is(1R,2R)-2-cyano-N-[(1S,5S)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;or, a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a compound which is(1R,2R)-2-{[(1R,5S)-3-{2-[(1-ethyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl}cyclopropanecarbonitrile;or, a pharmaceutically acceptable salt thereof.

In a certain other embodiment, the invention provides a compound whichis4-{(1R,5S)-8-[(2,2-difluorocyclopropyl)methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}-N-(1H-pyrazol-4-yl)pyrimidin-2-amine;or, a pharmaceutically acceptable salt thereof.

The invention further provides a pharmaceutical or a veterinarycomposition comprising a compound of formula I, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

The invention also provides a method for treating or preventing adisorder or condition selected from inflammation, autoimmune disease,neuroinflammation, arthritis, rheumatoid arthritis,spondyloarthropathies, systemic lupus erythematous, lupus nephritis,arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonarysarcoisosis, silicosis, cardiovascular disease, atherosclerosis,myocardial infarction, thrombosis, congestive heart failure and cardiacreperfusion injury, cardiomyopathy, stroke, ischaemia, reperfusioninjury, brain edema, brain trauma, neurodegeneration, liver disease,inflammatory bowel disease, Crohn's disease, ulcerative colitis,nephritis, retinitis, retinopathy, macular degeneration, glaucoma,diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterialinfection, myalgia, endotoxic shock, toxic shock syndrome, autoimmunedisease, osteoporosis, multiple sclerosis, endometriosis, menstrualcramps, vaginitis, candidiasis, cancer, fibrosis, obesity, musculardystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primarybiliary cirrhosis, primary sclerosing cholangitis, vitiligo, alopecia,Alzheimer's disease, skin flushing, eczema, psoriasis, atopic dermatitisand sunburn, comprising administering to the subject a therapeuticallyeffective amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable solvate ofsaid compound or salt.

In certain embodiments, the invention provides the method above whereinthe compound is selected from the group consisting of:

-   4-({4-[8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-5-fluoropyrimidin-2-yl}amino)-N-ethylbenzamide;-   N-ethyl-4-({5-fluoro-4-[8-(trifluoroacetyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-2-methylbenzamide;-   (1R,5S)-3-(2-{[5-methyl-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   (1R,5S)-N-(cyanomethyl)-3-(2-{[5-methyl-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;-   tert-butyl    3-(2-{[4-(ethylcarbamoyl)-3-methylphenyl]amino}-5-fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate;-   5-({4-[(1R,5S)-8-{[(1R,2R)-2-cyanocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;-   3-chloro-5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N-methylpyridine-2-carboxamide;-   N-(1-methyl-1H-pyrazol-4-yl)-4-[(1R,5S)-8-(1,2-thiazol-5-ylmethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-amine;-   5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3-methylpyridine-2-carboxamide;-   [(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-({6-[(2S)-1-hydroxypropan-2-yl]pyridin-3-yl}amino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;-   3-chloro-5-({4-[(1R,5S)-8-{[(1R,2R)-2-cyanocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N-methylpyridine-2-carboxamide;-   [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-(2-{[5-fluoro-6-(hydroxymethyl)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   5-[(4-{(1R,5S)-8-[(2,2-difluorocyclopropyl)carbonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}pyrimidin-2-yl)amino]-3-methylpyridine-2-carboxamide;-   5-({4-[(1R,5S)-8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;-   (1R,5S)-N-ethyl-3-(2-{[5-methyl-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   [(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-({6-[(2R)-1-hydroxypropan-2-yl]pyridin-3-yl}amino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;-   N-(1-methyl-1H-pyrazol-4-yl)-4-[(1R,5S)-8-(1,2-oxazol-5-ylmethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-amine;-   cyclopropyl{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;-   5-({4-[(1R,5S)-8-{[(1R,2R)-2-cyanocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;-   [(1R)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;-   5-({4-[(1R,5S)-8-{[(1R)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;-   N-ethyl-4-({5-fluoro-4-[6-(2-fluoro-2-methylpropanoyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2-yl}amino)-2-methylbenzamide;-   (1R)-2,2-difluoro-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   N-ethyl-2-methyl-4-({4-[6-(trifluoroacetyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2-yl}amino)benzamide;-   4-({4-[6-(2,2-difluoropropanoyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2-yl}amino)-N-ethylbenzamide;-   4-({4-[6-(cyclopropylcarbonyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2-yl}amino)-N-ethyl-2-methylbenzamide;-   N-{(1S,5R,6R)-3-[5-fluoro-2-({6-[(2R)-1-hydroxypropan-2-yl]pyridin-3-yl}amino)pyrimidin-4-yl]-6-methyl-3-azabicyclo[3.1.0]hex-1-yl}cyclopropanecarboxamide;-   N-[(1S,5R,6R)-3-(2-{[5-chloro-6-(hydroxymethyl)pyridin-3-yl]amino}-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;    and,-   N-[(1S,5R,6R)-3-(5-fluoro-2-{[6-(2-hydroxyethyl)pyridin-3-yl]amino}pyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

or, a pharmaceutically acceptable salt thereof.

In certain other embodiments, the invention provides a method fortreating or preventing psoriasis, vitiligo, alopecia, or atopicdermatitis by administering to a mammal in need a therapeuticallyeffective amount of a compound selected from the group consisting of:

-   [(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;-   [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;-   (1R,5S)-N-ethyl-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   [(1R)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   (1S)-2,2-difluoro-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   (1R,2R)-2-cyano-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   (1R,2R)-2-cyano-N-[(1    S,5S)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   (1R,2R)-2-{[(1R,5S)-3-{2-[(1-ethyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl}cyclopropanecarbonitrile;    and,-   4-{(1R,5S)-8-[(2,2-difluorocyclopropyl)methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}-N-(1H-pyrazol-4-yl)pyrimidin-2-amine;

or, a pharmaceutically acceptable salt thereof.

In other embodiments, the invention provides a method for treating orpreventing systemic lupus erythematosus or lupus nephritis byadministering to a mammal in need a therapeutically effective amount ofa compound selected from the group consisting of:

-   [(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;-   [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;-   (1R,5S)-N-ethyl-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   [(1R)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   (1S)-2,2-difluoro-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   (1R,2R)-2-cyano-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   (1R,2R)-2-cyano-N-[(1    S,5S)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   (1R,2R)-2-{[(1R,5S)-3-{2-[(1-ethyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl}cyclopropanecarbonitrile;    and,-   4-{(1R,5S)-8-[(2,2-difluorocyclopropyl)methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}-N-(1H-pyrazol-4-yl)pyrimidin-2-amine;

or, a pharmaceutically acceptable salt thereof.

In other embodiments, the invention provides a method for treating orpreventing primary biliary cirrhosis, autoimmune hepatitis, primarysclerosing cholangitis by administering to a mammal in need atherapeutically effective amount of a compound selected from the groupconsisting of:

-   [(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;-   [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;-   (1R,5S)-N-ethyl-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   [(1R)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   (1S)-2,2-difluoro-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   (1R,2R)-2-cyano-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   (1R,2R)-2-cyano-N-[(1    S,5S)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   (1R,2R)-2-{[(1R,5S)-3-{2-[(1-ethyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl}cyclopropanecarbonitrile;    and,-   4-{(1R,5S)-8-[(2,2-difluorocyclopropyl)methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}-N-(1H-pyrazol-4-yl)pyrimidin-2-amine;

or, a pharmaceutically acceptable salt thereof.

In certain other embodiments, the invention provides a method fortreating or preventing inflammatory bowel disease, Crohn's disease, orulcerative colitis by administering to a mammal in need atherapeutically effective amount of a compound selected from the groupconsisting of:

-   [(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;-   [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;-   (1R,5S)-N-ethyl-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   [(1R)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   (1S)-2,2-difluoro-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   (1R,2R)-2-cyano-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   (1R,2R)-2-cyano-N-[(1    S,5S)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   (1R,2R)-2-{[(1R,5S)-3-{2-[(1-ethyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl}cyclopropanecarbonitrile;    and,-   4-{(1R,5S)-8-[(2,2-difluorocyclopropyl)methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}-N-(1H-pyrazol-4-yl)pyrimidin-2-amine;

or, a pharmaceutically acceptable salt thereof.

In other embodiments, the invention provides a method for treating orpreventing multiple sclerosis by administering to a mammal in need atherapeutically effective amount of a compound selected from the groupconsisting of:

-   [(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;-   [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;-   (1R,5S)-N-ethyl-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;-   [(1R)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;-   (1S)-2,2-difluoro-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   (1R,2R)-2-cyano-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   (1R,2R)-2-cyano-N-[(1    S,5S)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;-   (1R,2R)-2-{[(1R,5S)-3-{2-[(1-ethyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl}cyclopropanecarbonitrile;    and,-   4-{(1R,5S)-8-[(2,2-difluorocyclopropyl)methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}-N-(1H-pyrazol-4-yl)pyrimidin-2-amine;

or, a pharmaceutically acceptable salt thereof.

The invention further provides a method of treating or preventing adisorder or condition selected from acute myeloid leukemia, T cell acutelymphoblastic leukemia, multiple myeloma, pancreatic cancer, braintumors, gliomas including astrocytoma, oligodendroglioma, andglioblastoma, acute CNS trauma including traumatic brain injury,encephalitis, stroke, and spinal cord injury, epilepsy, seizures, PD,ALS, frontotemporal lobe dementia, and with neuropsychiatric disordersincluding schizophrenia, bipolar disorder, depression, treatmentresistant depression, PTSD, anxiety, and auto-antibodies mediatedencephalopathies, comprising the step of administering to a subject aneffective amount of a composition comprising a compound of formula I, ora pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or salt.

The invention also provides a method of treating a disease or conditionfor which a JAK inhibitor is indicated, in a subject in need of suchtreatment, comprising administering to the subject a therapeuticallyeffective amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable solvate ofsaid compound or salt.

In certain embodiments, the therapeutically effective amount used inaccord with the method is from 0.01 mg/kg of body weight/day to 100mg/kg of body weight/day. In certain other embod-iments, thetherapeutically effective amount used in accord with the method iswherein the therapeutically effective amount is from 0.1 mg/kg of bodyweight/day to 10 mg/kg of body weight/day.

Compounds of the invention that have the same molecular formula butdiffer in the nature or sequence of bonding of their atoms or thearrangement of their atoms in space are termed “isomers”. Isomers thatdiffer in the arrangement of their atoms in space are termed“stereoisomers”. It will be appreciated by those skilled in the art thatthe compound of formula I can exist as cis- and trans-achiraldiastereomers.

Included within the scope of the described compounds are all isomers(e.g., cis-, trans-, or diastereomers) of the compounds described hereinalone as well as any mixtures. All of these forms, includingenantiomers, diastereomers, cis, trans, syn, anti, solvates (includinghydrates), tautomers, and mixtures thereof, are included in thedescribed compounds. Stereoisomeric mixtures, e.g., mixtures ofdiastereomers, can be separated into their corresponding isomers in aknown manner by means of suitable separation methods. Diastereomericmixtures for example may be separated into their individualdiastereomers by means of fractionated crystallization, chromatography,solvent distribution, and similar procedures. This separation may takeplace either at the level of one of the starting compounds or in acompound of formula I itself. Enantiomers may be separated through theformation of diastereomeric salts, for example by salt formation with anenantiomer-pure chiral acid, or by means of chromatography, for exampleby HPLC, using chromatographic substrates with chiral ligands. Thepresent invention includes all pharmaceutically acceptableisotopically-labelled compounds of formula I wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number whichpredominates in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S.

Certain isotopically-labelled compounds of formula I, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e., ³H,and carbon-14, i.e., ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e., ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof formula I can generally be prepared by conventional techniques knownto those skilled in the art or by processes analogous to those describedin the accompanying Examples and Preparations using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

In therapeutic use for treating disorders in a mammal, a compound of thepresent invention or its pharmaceutical compositions can be administeredorally, parenterally, topically, rectally, transmucosally, orintestinally. Parenteral administrations include indirect injections togenerate a systemic effect or direct injections to the afflicted area.Topical administrations include the treatment of skin or organs readilyaccessible by local application, for example, eyes or ears. It alsoincludes transdermal delivery to generate a systemic effect. The rectaladministration includes the form of suppositories. The preferred routesof administration are oral and parenteral.

Pharmaceutically acceptable salts of the compounds of formula I includethe acid addition and base salts thereof. Suitable acid addition saltsare formed from acids which form non-toxic salts. Examples include theacetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate,bisulfate/sulfate, borate, camsylate, citrate, cyclamate, edisylate,esylate, formate, fumarate, gluceptate, gluconate, glucuronate,hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate,saccharate, stearate, succinate, tannate, tartrate, tosylate,trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example,hemisulfate and hemicalcium salts. For a review on suitable salts, seeHandbook of Pharmaceutical Salts: Properties, Selection, and Use byStahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of compounds of formula I may beprepared, respectively, by one or more of three methods: (i) by reactingthe compound of formula I with the desired acid or base; (ii) byremoving an acid- or base-labile protecting group from a suitableprecursor of the compound of formula I or by ring-opening a suitablecyclic precursor, for example, a lactone or lactam, using the desiredacid or base; or (iii) by converting one salt of the compound of formulaI to another by reaction with an appropriate acid or base or by means ofa suitable ion exchange column. All three reactions are typicallycarried out in solution. The resulting salt may precipitate out and becollected by filtration or may be recovered by evaporation of thesolvent. The degree of ionization in the resulting salt may vary fromcompletely ionized to almost non-ionized.

Pharmaceutical compositions of the present invention may be manufacturedby methods well known in the art, e.g., by means of conventional mixing,dissolving, granulation, dragee-making, levigating, emulsifying,encapsulating, entrapping, lyophilizing processes or spray drying.

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morepharmaceutically acceptable carriers comprising excipients andauxiliaries, which facilitate processing of the active compound intopreparations, which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Pharmaceuticallyacceptable excipients and carriers are generally known to those skilledin the art and are thus included in the instant invention. Suchexcipients and carriers are described, for example, in Remington'sPharmaceutical Sciences, Mack Pub. Co., New Jersey (1991). Theformulations of the invention can be designed to be short-acting,fast-releasing, long-acting, and sustained-releasing. Thus, thepharmaceutical formulations can also be formulated for controlledrelease or for slow release.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in anamount sufficient to achieve the intended purpose, i.e., control or thetreatment of disorders or diseases. More specifically, a therapeuticallyeffective amount means an amount of compound effective to prevent,alleviate or ameliorate symptoms/signs of disease or prolong thesurvival of the subject being treated.

The quantity of active component, which is the compound of thisinvention, in the pharmaceutical composition and unit dosage formthereof, may be varied or adjusted widely depending upon the manner ofadministration, the potency of the particular compound and the desiredconcentration. Determination of a therapeutically effective amount iswell within the capability of those skilled in the art. Generally, thequantity of active component will range between 0.01% to 99% by weightof the composition.

Generally, a therapeutically effective amount of dosage of activecomponent will be in the range of about 0.01 to about 100 mg/kg of bodyweight/day, preferably about 0.1 to about 10 mg/kg of body weight/day,more preferably about 0.3 to 3 mg/kg of body weight/day, even morepreferably about 0.3 to 1.5 mg/kg of body weight/day It is to beunderstood that the dosages may vary depending upon the requirements ofeach subject and the severity of the disorders or diseases beingtreated.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

Also, it is to be understood that the initial dosage administered may beincreased beyond the above upper level in order to rapidly achieve thedesired plasma concentration. On the other hand, the initial dosage maybe smaller than the optimum and the daily dosage may be progressivelyincreased during the course of treatment depending on the particularsituation. If desired, the daily dose may also be divided into multipledoses for administration, e.g., two to four times per day.

Compounds of the present invention are directed to amino pyrimidinylcompounds useful as Janus Kinase inhibitors (JAK-i). They are useful astherapeutic agents in connection with the treating or preventing adisorder or condition selected from rheumatoid arthritis, myositis,vasculitis, pemphigus, Crohn's disease, ulcerative colitis, Alzheimer'sdisease, lupus, nephritis, psoriasis, atopic dermatitis, autoimmunethyroid disorders, multiple sclerosis, major depression disorder,allergy, asthma, Sjogren's disease, dry eye syndrome, organ transplantrejection, xeno transplantation, Type I diabetes and complications fromdiabetes, cancer, leukemia, T cell acute lymphoblastic leukemia, adult Tcell leukemia activated B-cell like, diffuse large B cell lymphoma,inflammatory bowel disease, septic shock, cardiopulmonary dysfunction,chronic pulmonary obstructive disorder, acute respiratory disease,cachexia, and other indications where immunosuppression/immunomodulationwould be desirable, comprising the step of administering to a subject aneffective amount of a compound of the invention.

There are substantial needs for safe and efficacious agents to controldisorders related to JAK, such as atopic dermatitis, both in human andanimals. The market for treating atopic dermatitis in animals iscurrently dominated by corticosteroids, which cause distressing andundesirable side effects in animals, specifically in companion animalssuch as dogs. Antihistamines are also used, but are poorly effective. Acanine formulation of cyclosporine (ATOPICA™) is currently beingmarketed for atopic dermatitis, but is expensive and has a slow onset ofefficacy. In addition, there are GI toleration issues with ATOPICA™.Compounds of the present invention are JAK inhibitors with selectiveefficacy against JAK1. These compounds are expected to provide analternative to steroid usage and provide resolution of chronic pruritusand inflammation that would either persist in atopic dermatitis orslowly regress following removal of allergen or causative agent, such asfleas in flea-allergic dermatitis.

The present invention also provides any of the uses, methods orcompositions as defined above wherein the compound of formula I, orpharmaceutically acceptable salt thereof, or pharmaceutically acceptablesolvate of said compound or salt, is used in combination with anotherpharmacologically active compound, particularly one of thefunctionally-defined classes or specific compounds listed below. Theseagents may be administered as part of the same or separate dosage forms,via the same or different routes of administration, and on the same ordifferent administration schedules according to standard pharmaceuticalpractice known to one skilled in the art.

Suitable agents for use in combination therapy with a compound offormula I, or pharmaceutically acceptable salt thereof, orpharmaceutically acceptable solvate of said compound or salt,particularly in the treatment of respiratory disease, include: a5-lipoxygenase activating protein (FLAP) antagonist; a leukotrieneantagonist (LTRA) such as an antagonist of LTB₄, LTC₄, LTD₄, LTE₄,CysLT₁ or CysLT₂, e.g., montelukast or zafirlukast; a histamine receptorantagonist, such as a histamine type 1 receptor antagonist or ahistamine type 2 receptor antagonist, e.g., loratidine, fexofenadine,desloratidine, levocetirizine, methapyrilene or cetirizine; anα1-adrenoceptor agonist or an α2-adrenoceptor agonist, e.g.,phenylephrine, methoxamine, oxymetazoline or methylnorephrine; amuscarinic M3 receptor antagonist, e.g. tiotropium or ipratropium; adual muscarinic M3 receptor antagononist/β2 agonist; a PDE inhibitor,such as a PDE3 inhibitor, a PDE4 inhibitor or a PDE5 inhibitor, e.g.,theophylline, sildenafil, vardenafil, tadalafil, ibudilast, cilomilastor roflumilast; sodium cromoglycate or sodium nedocromil; acyclooxygenase (COX) inhibitor, such as a non-selective inhibitor (e.g.,aspirin or ibuprofen) or a selective inhibitor (e.g. celecoxib orvaldecoxib); a glucocorticosteroid, e.g., fluticasone, mometasone,dexamethasone, prednisolone, budesonide, ciclesonide or beclamethasone;an anti-inflammatory monoclonal antibody, e.g., infliximab, adalimumab,tanezumab, ranibizumab, bevacizumab or mepolizumab; a β2 agonist, e.g.,salmeterol, albuterol, salbutamol, fenoterol or formoterol, particularlya long-acting β2 agonist; an intigrin antagonist, e.g., natalizumab; anadhesion molecule inhibitor, such as a VLA-4 antagonist; a kinin B₁ orB₂ receptor antagonist; an immunosuppressive agent, such as an inhibitorof the IgE pathway (e.g., omalizumab) or cyclosporine; a matrixmetalloprotease (MMP) inhibitor, such as an inhibitor of MMP-9 orMMP-12; a tachykinin NK₁, NK₂ or NK₃ receptor antagonist; a proteaseinhibitor, such as an inhibitor of elastase, chymase or catheopsin G; anadenosine A_(2a) receptor agonist; an adenosine A_(2b) receptorantagonist; a urokinase inhibitor; a dopamine receptor agonist (e.g.,ropinirole), particularly a dopamine D2 receptor agonist (e.g.,bromocriptine); a modulator of the NFκB pathway, such as an IKKinhibitor; a further modulator of a cytokine signalling pathway such asan inhibitor of JAK kinase, syk kinase, p38 kinase, SPHK-1 kinase, Rhokinase, EGF-R or MK-2; a mucolytic, mucokinetic or anti-tussive agent;an antibiotic; an antiviral agent; a vaccine; a chemokine; an epithelialsodium channel (ENaC) blocker or Epithelial sodium channel (ENaC)inhibitor; a nucleotide receptor agonist, such as a P2Y2 agonist; athromboxane inhibitor; niacin; a 5-lipoxygenase (5-LO) inhibitor, e.g.,Zileuton; an adhesion factor, such as VLAM, ICAM or ELAM; a CRTH2receptor (DP₂) antagonist; a prostaglandin D₂ receptor (DP₁) antagonist;a haematopoietic prostaglandin D2 synthase (HPGDS) inhibitor;interferon-β; a soluble human TNF receptor, e.g., Etanercept; a HDACinhibitor; a phosphoinositotide 3-kinase gamma (PI3Kγ) inhibitor; aphosphoinositide 3-kinase delta (PI3Kδ) inhibitor; a CXCR-1 or a CXCR-2receptor antagonist; an IRAK-4 inhibitor; and, a TLR-4 or TLR-9inhibitor, including the pharmaceutically acceptable salts of thespecifically named compounds and the pharmaceutically acceptablesolvates of said specifically named compounds and salts.

Accordingly, the invention provides methods of treating or preventing adisease, condition or disorder associated with JAK in a subject, such asa human or non-human mammal, comprising administering an effectiveamount of one or more compounds described herein to the subject.Suitable subjects that can be treated include domestic or wild animals,companion animals, such as dogs, cats, horses and the like; livestockincluding, cows and other ruminants, pigs, poultry, rabbits and thelike; primates, for example monkeys, such as rhesus monkeys andcynomolgus (also known as crab-eating or long-tailed) monkeys,marmosets, tamarins, chimpanzees, macaques and the like; and rodents,such as rats, mice, gerbils, guinea pigs and the like. In oneembodiment, the compound is administered in a pharmaceuticallyacceptable form, optionally in a pharmaceutically acceptable carrier.

Conditions in which selective targeting of the JAK pathway or modulationof the JAK kinases, particularly JAK1, are contemplated to betherapeutically useful include, arthritis, asthma, autoimmune diseases,cancers or tumors, diabetes, certain eye diseases, disorders orconditions, inflammation, intestinal inflammations, allergies orconditions, neurodegenerative diseases, psoriasis, and transplantrejection. Conditions which can benefit from selective inhibition ofJAK1 are discussed in greater detail below.

Accordingly, the compound of formula I or its pharmaceuticallyacceptable salts, and pharmaceutical compositions thereof can be used totreat a variety of conditions or diseases such as the following:

Arthritis, including rheumatoid arthritis, juvenile arthritis, andpsoriatic arthritis;

Autoimmune diseases or disorders, including those designated as singleorgan or single cell-type autoimmune disorders, for example Hashimoto'sthyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritisof pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis,Goodpasture's disease, autoimmune thrombocytopenia, sympatheticophthalmia, myasthenia gravis, Graves' disease, primary biliarycirrhosis, chronic aggressive hepatitis, ulcerative colitis andmembranous glomerulopathy, those designated as involving systemicautoimmune disorder, for example systemic lupus erythematosis,rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome,polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa,multiple sclerosis and bullous pemphigoid, and additional autoimmunediseases, which can be O-cell (humoral) based or T-cell based, includingCogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis,autoimmune alopecia, Type I or juvenile onset diabetes, or thyroiditis;

Cancers or tumors, including alimentary/gastrointestinal tract cancer,colon cancer, liver cancer, skin cancer including mast cell tumor andsquamous cell carcinoma, breast and mammary cancer, ovarian cancer,prostate cancer, lymphoma, leukemia, including acute myelogenousleukemia and chronic myelogenous leukemia, kidney cancer, lung cancer,muscle cancer, bone cancer, bladder cancer, brain cancer, melanomaincluding oral and metastatic melanoma, Kaposi's sarcoma, myelomasincluding multiple myeloma, myeloproliferative disorders, proliferativediabetic retinopathy, or angiogenic-associated disorders including solidtumors;

Diabetes, including Type I diabetes or complications from diabetes;

Eye diseases, disorders or conditions including autoimmune diseases ofthe eye, keratoconjunctivitis, vernal conjunctivitis, uveitis includinguveitis associated with Behcet's disease and lens-induced uveitis,keratitis, herpetic keratitis, conical keratitis, corneal epithelialdystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis,Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome,keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis,sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis,allergic conjunctivitis, or ocular neovascularization;

Intestinal inflammations, allergies or conditions including Crohn'sdisease and/or ulcerative colitis, inflammatory bowel disease, celiacdiseases, proctitis, eosinophilic gastroenteritis, or mastocytosis;

Neurodegenerative diseases including motor neuron disease, Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, cerebral ischemia, or neurodegenerative diseasecaused by traumatic injury, strike, glutamate neurotoxicity or hypoxia;ischemic/reperfusion injury in stroke, myocardial ischemica, renalischemia, heart attacks, cardiac hypertrophy, atherosclerosis andarteriosclerosis, organ hypoxia, or platelet aggregation;

Skin diseases, conditions or disorders including atopic dermatitis,eczema, psoriasis, scleroderma, pruritus or other pruritic conditions,vitiligo, alopecia;

Allergic reactions including allergic dermatitis in mammal (includinghorse allergic diseases such as bite hypersensitivity), summer eczema,sweet itch in horses, heaves, inflammatory airway disease, recurrentairway obstruction, airway hyper-responsiveness, or chronic obstructionpulmonary disease;

Asthma and other obstructive airways diseases, including chronic orinveterate asthma, late asthma, bronchitis, bronchial asthma, allergicasthma, intrinsic asthma, extrinsic asthma, or dust asthma;

Transplant rejection, including pancreas islet transplant rejection,bone marrow transplant rejection, graft-versus-host disease, organ andcell transplant rejection such as bone marrow, cartilage, cornea, heart,intervertebral disc, islet, kidney, limb, liver, lung, muscle, myoblast,nerve, pancreas, skin, small intestine, or trachea, or xenotransplantation.

Chemical Synthesis

The following schemes and written descriptions provide general detailsregarding the preparation of the compounds of the invention.

The compounds of the invention may be prepared by any method known inthe art for the preparation of compounds of analogous structure. Inparticular, the compounds of the invention can be prepared by theprocedures described by reference to the schemes that follow, or by thespecific methods described in the examples, or by similar processes toeither.

The skilled person will appreciate that the experimental conditions setforth in the schemes that follow are illustrative of suitable conditionsfor effecting the transformations shown, and that it may be necessary ordesirable to vary the precise conditions employed for the preparation ofcompounds of formula (I).

In addition, the skilled person will appreciate that it may be necessaryor desirable at any stage in the synthesis of compounds of the inventionto protect one or more sensitive groups, so as to prevent undesirableside reactions. In particular, it may be necessary or desirable toprotect amino or carboxylic acid groups. The protecting groups used inthe preparation of the compounds of the invention may be used inconventional manner. See, for example, those described in ProtectiveGroups in Organic Synthesis by Theodora W. Greene and Peter G. M. Wuts,3rd edition, (John Wiley and Sons, 1999), in particular chapters 7(“Protection for the Amino Group”) and 5 (“Protection for the CarboxylGroup”), incorporated herein by reference, which also describes methodsfor the removal of such groups.

All of the derivatives of formula I can be prepared by the proceduresdescribed in the general methods presented below or by routinemodifications thereof. The present invention also encompasses any one ormore of these processes for preparing the derivatives of formula (I), inaddition to any novel intermediates used therein. The person skilled inthe art will appreciate that the following reactions may be heatedthermally or under microwave irradiation.

It will be further appreciated that it may be necessary or desirable tocarry out the transformations in a different order from that describedin the schemes, or to modify one or more of the transformations, toprovide the desired compound of the invention.

According to a first process, compounds of formula (IA) may be preparedfrom compounds of formulae (VI) and (V), as illustrated by Scheme 1.

Wherein PG is tert-butoxycarbonyl; X is chloro, hydroxyl, a suitableleaving group or a suitable anhydride Z═(CH₂)_(h); A is —N(C═O)R⁰—;

Compounds of formulae (VI), (V), (VIII) and (VII) are commerciallyavailable or may be synthesized by those skilled in the art according tothe literature or preparations described herein. Compounds of formula(IA) may be separated into the respective enantiomers via chiralseparation of the racemate as required. Wherein R⁴ contains a protectinggroup such as tert-butoxycarbonyl or tosyl, suitable deprotectionconditions may be employed as necessary. Preferred conditions comprise4M HCl in dioxane or 5N NaOH in dioxane.

Compounds of formula (IA) may be prepared from compounds of formula (II)according to process step (iv), a nucleophilic substitution reactionwith compounds of formula (VII) under either Buchwald-Hartwig crosscoupling conditions or mediated by acid and high temperatures. TypicalBuchwald-Hartwig conditions comprise a suitable palladium catalyst witha suitable chelating phosphine ligand with an inorganic base in asuitable organic solvent at elevated temperatures either thermally orunder microwave irradiation. Preferred conditions comprisetris(dibenzylideneacetone)dipalladium (0) and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl or xantphos orRuPHOS palladium (II) phenethylamine chloride with sodium tert-butoxideor potassium phosphate or cesium carbonate in tert-amyl alcohol or DMSOat from 120-140° C. under microwave irradiation. Typical acidicconditions comprise a suitable inorganic acid in a suitable alcoholicsolvent at elevated temperatures either thermally or under microwaveirradiation. Preferred conditions comprise concentrated hydrochloricacid in iso-propanol at 140° C. under microwave irradiation.

Compounds of formula (II) may be prepared from compounds of formula(III) according to process step (iii), an amide bond formation reactionwith compounds of formula (VIII), wherein X may be chloro, hydroxyl, asuitable leaving group or anhydride. Wherein compounds of formula (VIII)are acid chlorides, preferred conditions comprise triethylamine in DCMat room temperature. Wherein compounds of formula (VIII) are carboxylicacids, activation of the carboxylic acid using a suitable inorganic baseand a suitable coupling agent is employed. Preferred conditions compriseDIPEA or triethylamine with HATU in DCM or DMF at room temperature.Wherein compounds of formula (VIII) are anhydrides, preferred conditionscomprise stirring in DCM at room temperature. Wherein compounds offormula (VII) contain suitable leaving groups such aspara-chlorophenoxy, preferred conditions comprise DIPEA in dioxane atreflux.

Compounds of formula (III) may be prepared from compounds of formula(IV) according to process step (ii) a deprotection reaction mediated byeither an inorganic or organic acid in a suitable organic solvent.Preferred conditions comprise hydrochloric acid or THE in dioxane orDCM. Compounds of formula (IV) may be prepared from compounds offormulae (V) and (VI) according to process step (i), an aromaticnucleophilic substitution reaction in the presence of an inorganic base.Preferred conditions comprise triethylamine in methanol at from 0° C. toroom temperature.

According to a second process, compounds of formula (IA) may be preparedfrom compounds of formula (IV) as illustrated by Scheme 2

Wherein PG is tert-butoxycarbonyl; X is chloro, hydroxyl, a suitableleaving group or a suitable anhydride; Z═(CH₂)_(h); A is —N(C═O)R⁰—.

Compounds of formula (IV) may be prepared as described in Scheme 1.

Compounds of formulae (VIII) and (VII) are commercially available or maybe synthesized by those skilled in the art according to the literatureor preparations described herein. Compounds of formula (IA) may beprepared from compounds of formula (IV) by reversing the steps shown inScheme 1. Compounds of formula (IA) may be prepared from compounds offormulae (XI) and (VIII) according to process step (iii), an amide bondformation reaction as described in Scheme 1.

Compounds of formula (XI) may be prepared from compounds of formula (IV)according to process steps (iv) and (ii), a nucleophilic substitutionreaction with compounds of formula (VII) under either Buchwald-Hartwigcross coupling conditions or mediated by acid and high temperaturesfollowed by a deprotection reaction mediated by either an inorganic ororganic acid as described in Scheme 1. Alternatively the deprotectionoccurs in situ during process step (iv).

According to a third process, compounds of formula (IA) may be preparedfrom compounds of formula (XI) as illustrated by Scheme 3.

Wherein A is NR⁰; Z═(CH₂)_(h); LG is leaving group such as chloro,bromo, iodo, tosylate, mesylate.

Compounds of formula (XI) may be prepared as described in Scheme 1.Compounds of formula (X), (XII) and (XIII) are commercially available ormay be synthesized by those skilled in the art according to theliterature or preparations described herein. Compounds of formula (IA)may be prepared from compounds of formula (XI) according to eitherprocess step (v), a reductive amination reaction with aldehydes orketones of formula (X) or process step (vi), a Michael addition reactionwith conjugated alkenes of formula (XII) or process step (vii), analkylation reaction with compounds of formula (XIII). Preferredconditions for the reductive amination comprise sodiumtriacetoxyborohydride or sodium cyanoborohydride in MeOH either with orwithout an inorganic base and an inorganic acid; such as triethylamineand acetic acid. Preferred conditions for the Michael addition comprisestirring compounds of formula (XI) with conjugated alkenes of formula(XII) in ethanol at from 0-140° C. either thermally or under microwaveirradiation. Preferred conditions for the alkylation reaction comprisestirring compounds of formula (XI) with compounds of formula (XIII) thatcontain a suitable leaving group for alkylation with an inorganic basesuch as sodium carbonate with a catalyst such as tert-butylammoniumiodide.

According to a fourth process, compounds of formula (IA) may be preparedfrom compounds of formula (XI) as illustrated by Scheme 4.

Wherein A is NR⁰, Z═(CH₂)_(h); wherein R⁰ is heteroaryl; Hal is fluoro,chloro, bromo, iodo.

Compounds of formula (XI) may be prepared as described in Scheme 1.Compounds of formula (XIV) are commercially available or may besynthesized by those skilled in the art according to the literature orpreparations described herein. Compounds of formula (IA) may be preparedfrom compounds of formula (XI) according to process step (iv) an anucleophilic substitution reaction with compounds of formula (XIV) undereither Buchwald-Hartwig cross coupling conditions as described in Scheme1 or mediated by base and high temperatures. Preferred conditionsmediated by base and high temperatures comprise triethylamine inisopropanol at 160° C. under microwave irradiation.

According to a fifth process, compounds of formula (IA) may be preparedfrom compounds of formula (XI) as illustrated by Scheme 5.

Wherein A is NSO₂R⁰; Z═(CH₂)_(h).

Compounds of formula (XI) may be prepared as described in Scheme 1.Compounds of formula (XV) are commercially available or may besynthesized by those skilled in the art according to the literature orpreparations described herein. Compounds of formula (IA) may be preparedfrom compounds of formula (XI) according to process step (viii) asulfonamide formation reaction with compounds of formula (XV). Preferredconditions comprise triethylamine in DCM at room temperature.

According to a sixth process, compounds of formula (IA) may be preparedfrom compounds of formula (XI) as illustrated by Scheme 6.

Wherein A is —N(C═O)NHR⁰—; Z═(CH₂)_(h).

Compounds of formula (XI) may be prepared as described in Scheme 1.Compounds of formula (XVI) and (XVII) are commercially available or maybe synthesized by those skilled in the art according to the literatureor preparations described herein.

Compounds of formula (IA) may be prepared from compounds of formula (XI)according to process step (ix), a urea formation reaction withisocyanates of formula (XVI) or imidazoureas of formula (XVII).Preferred conditions comprise triethylamine in DCM at temperatures from−50° C. to room temperature.

According to a seventh process, compounds of formula (IA) may also beinterconverted to other compounds of formula (IA) as illustrated belowin Scheme 7.

Wherein Z═(CH₂)_(h).

Compounds of formula (IAi) may be prepared as for compounds of formula(IA) as described in Schemes 1-5. Compounds of formula (IAii) may beprepared from compounds of formula (IAi) according to process steps (ii)and (viii), a deprotection step followed by a sulfonamide formationreaction as described in Schemes 1 and 5. According to an eighthprocess, compounds of formula (IAiv) may also be interconverted to othercompounds of formula (IAiii) as illustrated below in Scheme 8.

Wherein Z═(CH₂)_(h).

Compounds of formula (IAiv) may be prepared as for compounds of formula(IA) as described in Schemes 1-5. Compounds of formula (IAiii) may beprepared from compounds of formula (IAiv) according to process step (x),a dehydration reaction via a primary carboxamide. Preferred conditionscomprise 7M ammonia in methanol at elevated temperatures of 90° C.followed by dehydration with TFAA.

According to a ninth process, compounds of formula (IB) may be preparedfrom compounds of formula (XXIII) as illustrated by Scheme 9.

Wherein R^(x) is H or Methyl, R^(y) is H or CH₂OH, PG¹ istert-butoxycarbonyl; PG² is benzyl; X is chloro, hydroxyl, a suitableleaving group or a suitable anhydride.

Compounds of formula (XXIII), (VI), (XVIII) and (VII) are commerciallyavailable or may be synthesized by those skilled in the art according tothe literature or preparations described herein. Compounds of formula(IB) may be separated into the respective enantiomers via chiralseparation of the racemate as required. Compounds of formula (IB) may beprepared from compounds of formula (XIX) and (VII) according to processstep (iv) a nucleophilic substitution reaction with compounds of formula(VII) under either Buchwald-Hartwig cross coupling conditions ormediated by acid and high temperatures as described in Scheme 1.

Compounds of formula (IB) may also be prepared from compounds of formula(XX) and (XVIII) according to process step (iii) an acylation reactionas described in Scheme 1. Compounds of formula (XIX) may be preparedfrom compounds of formula (XXI) and (VI) according to process steps (ii)and (i), a deprotection reaction followed by an aromatic nucleophilicsubstitution reaction as described in Scheme 1. and as illustrated byScheme 10. Compounds of formula (XIX) may be prepared from compounds offormula (XXIII) and (XVIII) according to process step (iii), an amidebond formation reaction as described in Scheme 1.

According to a tenth process, compounds of formula (IB) may be preparedfrom compounds of formula (XXIII) as illustrated by Scheme 10.

Wherein R^(x) is H or Methyl, R^(y) is H or CH₂OH, PG¹ istert-butoxycarbonyl; PG² is benzyl; X is chloro, hydroxyl, a suitableleaving group or a suitable anhydride. Compounds of formula (XX) may beprepared from compounds of formula (XXII) and (VII) according to processsteps (ii) and (iv), a deprotection reaction and a nucleophilicsubstitution reaction with compounds of formula (VII) under eitherBuchwald-Hartwig cross coupling conditions or mediated by acid and hightemperatures as described in Scheme 1. Deprotection may also occurduring the process of reaction step (iv).

Compounds of formula (XXII) may be prepared from compounds of formula(XXIV) and (VI) according to process step (i) an aromatic nucleophilicsubstitution reaction as described in Scheme 1. Compounds of formula(XXIV) may be prepared from compounds of formula (XXIII) according toreaction steps (xi) and (xii), suitable deprotection and protectionsteps as necessary. Preferred protection conditions comprisedi-tert-butyl dicarbonate with triethylamine at room temperaturefollowed by deprotection of an orthogonal protecting group underhydrogenation over a metal catalyst. Preferred conditions comprisehydrogenation at 50 psi at room temperature over palladium hydroxide.

According to a eleventh process, Compounds of formula (IA) may beprepared from compounds of formulae (XXX) and (VIII), as illustrated byScheme 11.

Wherein PG is tert-butoxycarbonyl; LG is a leaving group such as chloro,bromo, iodo, tosylate, mesylate; W is a hydroxyl or thiolether; X ischloro, hydroxyl, a suitable leaving group or a suitable anhydride;Z═(CH₂)_(h); A is —N(C═O)R⁰—;

Compounds of formula (XXX), (XXVII), and (VII) are commerciallyavailable or may be synthesized by those skilled in the art according tothe literature or preparations described herein, Compounds of formula(IA) may be prepared from compounds of formula (XXV) and (VII) accordingto process (iii), an amide bond formation reaction as described inScheme 1.

Compounds of formula (XXV) can be prepared from compounds of formula(XXVIII) and (XXVII) according to process (iv), a nucleophilicsubstitution reaction as described in Scheme 1.

Compounds of formula (XXVIII) can be prepared from compounds of formula(XXIX) according to process (xiii), halogenation mediated by phosphorylhalides. Typical conditions comprise of reaction of a phoshoryl halidewith or without additional solvent at room temperature or heated.Preferred conditions for conversion of an alcohol to halide comprise ofphosphoryl chloride and heated to reflux.

Compound of formula (XXIX) can be prepared from compounds of formula(XXX) and (VII) according to process (ii), a nucleophilic substitutionreaction as described in Scheme 1.

In executing the synthesis of the compounds of the invention, oneskilled in the art will recognize the need to sample and assay reactionmixtures prior to work up in order to monitor the progress of reactionsand decide whether the reaction should be continued or whether it isready to be worked up to obtain the desired product. Common methods forassaying reaction mixtures include thin-layer chromatography (TLC),liquid chromatography/mass spectroscopy (LCMS), and nuclear magneticresonance (NMR).

One skilled in the art will also recognize that the compounds of theinvention may be prepared as mixtures of diastereomers or geometricisomers (e.g., cis and trans substitution on a cycloalkane ring). Theseisomers can be separated by standard chromatographic techniques, such asnormal phase chromatography on silica gel, reverse phase preparativehigh pressure liquid chromatography or supercritical fluidchromatography. One skilled in the art will also recognize that somecompounds of the invention are chiral and thus may be prepared asracemic or scalemic mixtures of enantiomers. Several methods areavailable and are well known to those skilled in the art for theseparation of enantiomers. A preferred method for the routine separationenantiomers is supercritical fluid chromatography employing a chiralstationary phase.

EXPERIMENTAL SECTION

Except where otherwise noted, reactions were run under an atmosphere ofnitrogen. Chromatography on silica gel was carried out using 250-400mesh silica gel using pressurized nitrogen (˜10-15 psi) to drive solventthrough the column (“flash chromatography”). Where indicated, solutionsand reaction mixtures were concentrated by rotary evaporation undervacuum.

¹H and ¹⁹F Nuclear magnetic resonance (NMR) spectra were in all casesconsistent with the proposed structures. Characteristic chemical shifts(δ) are given in parts-per-million downfield from tetramethylsilane (for¹H-NMR) and upfield from trichlorofluoromethane (for ¹⁹F NMR) usingconventional abbreviations for designation of major peaks: e.g., s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.The following abbreviations have been used for common solvents: CDCl₃,deuterochloroform; d₆-DMSO, deuterodimethylsulfoxide; and CD₃OD,deuteromethanol. Where appropriate, tautomers may be recorded within theNMR data; and some exchangeable protons may not be visible. Massspectra, MS (m/z), were recorded using either electrospray ionization(ESI) or atmospheric pressure chemical ionization (APCI). Where relevantand unless otherwise stated the m/z data provided are for isotopes ¹⁹F³⁵Cl, ⁷⁹Br and ¹²⁷I.

The nomenclature in this patent is written as described by IUPAC(International Union of Pure and Applied Chemistry and using ACD/NameVersion 12 (Toronto, Canada) to generate names.

In the non-limiting Examples and Preparations that are set out later inthe description, and in the aforementioned Schemes, the following theabbreviations, definitions and analytical procedures may be referred to:

CDI is carbonyl di-imidazole;

DBU is diazabicyclo[5.4.0]undec-7-ene;

DCC is N,N′-dicyclohexylcarbodiimide;

DCM is dichloromethane; methylene chloride;

DEAD is diethylazodicarboxylate;

DIPEA/DIEA is N-ethyldiisopropylamine, N,N-diisopropylethylamine;

DMA is dimethylacetamide;

DMAP is dimethylaminopyridine;

DPPP is 1,3-bis(diphenylphosphino)propane;

EDCl⋅HCl is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

ee is enantiomeric excess;

HATU is1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate;

HOBt is hydroxybenzotriazole;

LCMS is liquid chromatography mass spectrometry (Rt=retention time);

Pd₂(dba)₃ is trisdibenzylideneacetonedipalladium;

Pd(dppf)Cl2 is1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride;

RuPHOS is 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl;

TBDMS is tertbutyldimethylsilyl;

TLC is thin layer chromatography;

Xantphos/Xphos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

GCMS Conditions

Column: 12 m×0.2 mm, HP-1 Methyl Siloxane, 0.33 μm film, 1.0 m/mincolumn flow

Method: 7.6 min: Initial Oven Temp 105° C.; 0.1 min hold; 30° C./minramp to 300° C. endpoint at 7.6 min or 7.6 min: Initial Oven Temp 60°C.; 0.1 min hold; 40° C./min ramp to 320° C. endpoint at 7.6 min or 5.1min:

Initial Oven Temp 40° C.; 0.1 min hold; 30° C./min ramp to 150° C.endpoint at 5.1 min

GC Inlet Parameters: Front Inlet, Split 30:1, He, 8 psi pressure, 250°C. Injector, 33.9 ml/min total flow

MSD Tune: 230° C. Source Temp, 150° C. Quad Temp, 280° C. Aux2 Temp

Injection Volume: 1.0 μL

System Components: Agilent 5890 GC Oven with Agilent 5973 Mass SelectiveDetector

LCMS Conditions

Acid: Waters Acquity HSS T3, 2.1 mm×50 mm, C18, 1.7 μm; ColumnTemperature 60° C.

Base: Waters Acquity UPLC BEH, 2.1 mm×50 mm, C18, 1.8 μm; ColumnTemperature 60° C.

Mobile Phase: A: 0.1% formic acid in water (v/v); Mobile phase B: 0.1%formic acid in acetonitrile (v/v).

Mobile Phase A: 0.1% ammonia in water (v/v); Mobile phase B: 0.1%ammonia in acetonitrile (v/v) Gradient Profiles:

1.5 min Run: Initial conditions: A-95%:B-5%; hold at initial from0.0-0.1 min; Linear Ramp to A-5%:B-95% over 0.1-1.0 min; hold atA-5%:B-95% from 1.0-1.1 min; return to initial conditions 1.1-1.5 min

¹H and ¹⁹F Nuclear magnetic resonance (NMR) spectra were in all casesconsistent with the proposed structures. Characteristic chemical shifts(b) are given in parts-per-million downfield from tetramethylsilane (for¹H-NMR) and upfield from trichloro-fluoro-methane (for ¹⁹F NMR) usingconventional abbreviations for designation of major peaks: e.g., s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.The following abbreviations have been used for common solvents: CDCl₃,deuterochloroform; d₆-DMSO, deuterodimethylsulphoxide; and CD₃OD,deuteromethanol. Where appropriate, tautomers may be recorded within theNMR data; and some exchangeable protons may not be visible.

Mass spectra, MS (m/z), were recorded using either electrosprayionisation (ESI) or atmospheric pressure chemical ionisation (APCI).Where relevant and unless otherwise stated the m/z data provided are forisotopes ¹⁹F, ³⁵Cl, ⁷⁹Br and ¹²⁷I. Where preparative TLC or silica gelchromatography has been used, one skilled in the art may choose anycombination of solvents to purify the desired compound.

Purification Methods (PM)

The compounds of the Examples were purified according to one of thePurification Methods (PM) referred to below unless otherwise described:

Purification Method A: Preparative HPLC using [Agella venusil ASB C18150×21.2 mm×5 μm, from 16% MeCN in water (0.225% formic acid) to 36%MeCN in water (0.225% formic acid)]

Purification Method B: Preparative HPLC using [Phenomenex Gemini C18250×21.2 mm×8 um or 150 mm×25 mm×5 μm; from 16-55% MeCN in water (0.1%ammonia) to 36-60% MeCN in water (0.1% ammonia)]

Purification Method C: [YMC-Actus Triad C18 150×30 μm, from 24% MeCN inwater (0.1% ammonia) to 44% MeCN in water (0.1% ammonia)]

Purification Method D: Preparative HPLC using [Phenomenex Gemini C18250×21.2 mm×8 μm, from 25% MeCN in water (ammonia pH=10) to 45% MeCN inwater (ammonia pH=10)] followed by chiral chromatography using AS 250×25mm I.D. 20 μM column, with supercritical CO₂: EtOH or IPA (0.05% aqueousammonia) 70:30 at from 50-80 mL/minPurification Method E: Preparative HPLC using [Phenomenex Gemini C18250×21.2 mm×8 μm, from 25% MeCN in water (0.225% ammonia) to 45% MeCN inwater (0.225% ammonia) followed by chiral chromatography using AD 250mm×30 mm×20 μm column with mobile phase A: supercritical CO₂ and mobilephase B MeOH with 0.1% ammonia A:B 50:50 at 180 mL/minPurification Method F: Silica gel column chromatography eluting with100% DCM to 12% MeOH with 1% NH₄OH.Purification Method G: Silica gel column chromatography eluting with97:2:1 DCM:MeOH:NH₃ followed by preparative HPLC.Purification Method H: Preparative HPLC using Column: Waters XBridge C1819 mm×100 mm, 5μ; Mobile phase A: 0.03% ammonium hydroxide in water(v/v); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v);from 5-20% B to 40-100% B at 25 mL/min flow rate.Purification Method I: Preparative HPLC using Column: Waters Sunfire C1819 mm×100 mm, 5μ; Mobile phase A: 0.05% TFA in water (v/v); Mobile phaseB: 0.05% TFA in acetonitrile (v/v); from 20% B to 40% B at 6.75 minutes,then to 100% B at 7 minutes at 30 mL/min flow rate.Specific Rotation

Specific rotations based on the equation [α]=(100·α)/(l·c) and arereported as unitless numbers where the concentration c is in g/100 mLand the path length l is in decimeters. The units of the specificrotation, (deg·mL)/(g·dm), are implicit and are not included with thereported value.

Library Protocol 1

A 0.2M solution of((1R,5S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone(Preparation 27, 500 μl, 100 μmol) in tert-amyl alcohol was added toamines of formula (R⁴NH₂) (150 μmol) followed by sodium tert-butoxide(200 μmol), Pd₂(dba)₃ (2 μmol) and XPhos (2 μmol) under nitrogen. Thereactions were heated to 140° C. under microwave irradiation for 40minutes. The reactions were cooled, concentrated in vacuo and purifiedusing preparative HPLC.

Preparative HPLC

Purification Method 1 (PM1): Phenomenex Gemini C18, 250×21.2 mm×8 μm;Acetonitrile-ammonium hydroxide; Flow rate 30 mL/min; Gradient time 8mins.

Purification Method 2 (PM2): DIKMA Diamonsil C18 200 mm×20 mm×5 μm;MeCN-water (0.225% formic acid); Flow rate 35 mL/min; Gradient time 9mins.

LCMS Method:

Column: XBridge C18 2.1 mm×50 mm×5 μm

Mobile Phase A: 0.05% ammonium hydroxide in water

Mobile phase B: 100% MeCN

Gradient: 5% B to 100% B at 3.40 minutes then back to 5% B at 4.21minutes.

Flow rate: 0.8 mL/min

The compounds of the Examples in the table below were prepared from((1R,5S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone(Preparation 27) and the appropriate amine according to Library Protocol1.

Ex Name SM/Data/HPLC Organic gradient 1 cyclopropyl{(1R,5S)-3-[5-Pyridazin-4-amine fluoro-2-(pyridazin-4- Rt = 2.31 minutesylamino)pyrimidin-4-yl]-3,8- MS m/z 370 [M + H]⁺diazabicyclo[3.2.1]oct-8- 17-47% organic in PM 1. yl}methanone 23-({4-[(1R,5S)-8- 5-amino-1H-pyrazole-3- (cyclopropylcarbonyl)-3,8-carboxylic acid propylamide diazabicyclo[3.2.1]oct-3-yl]- (Preparation83). 5-fluoropyrimidin-2-yl}amino)- Rt = 2.45 minutesN-propyl-1H-pyrazole-5- MS m/z 443 [M + H]⁺ carboxamide 11-41% organicin PM 2. 3 6-({4-[(1R,5S)-8- 7-amino-imidazo[1,2-a]pyridine-(cyclopropylcarbonyl)-3,8- 2-carboxylic aciddiazabicyclo[3.2.1]oct-3-yl]- amide(Preparation 86).5-fluoropyrimidin-2- Rt = 2.22 minutes yl}amino)imidazo[1,2- MS m/z 451[M + H]⁺ a]pyridine-2-carboxamide 10-40% organic in PM 2. 45-({4-[(1R,5S)-8- 2-(methylsulfonyl)-pyridin- (cyclopropylcarbonyl)-3,8-4-amine diazabicyclo[3.2.1]oct-3-yl]- Rt = 2.35 minutes5-fluoropyrimidin-2- MS m/z 448 [M + H]⁺ yl}amino)pyridine-2- 13-53%organic in PM 1. sulfonamide

Example 5(1R,5S)-N-ethyl-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

To a solution of(1R,5S)-3-(2-chloropyrimidin-4-yl)-N-ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxamide(Preparation 29, 184 mg, 0.624 mmol) and tert-butyl4-amino-1H-pyrazole-1-carboxylate (PCT Publication No. WO2012022681, 126mg, 0.686 mmol) in DMA (8 mL) was added Cs₂CO₃ (405.6 mg, 1.248 mmol),Pd(OAc)₂ (28 mg, 0.124 mmol) and xantphos (72 mg, 0.124 mmol). Thereaction was purged with nitrogen for 3 minutes before heating to 120°C. under microwave irradiation for 1 hour. The reaction was concentratedin vacuo and purified by silica gel column chromatography eluting with10% MeOH in DCM followed by preparative HPLC (Purification Method B) toafford the title compound (81 mg, 38%).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.02 (t, 3H), 1.58 (d, 2H), 1.77 (d,2H), 2.96-3.11 (m, 4H) 3.79-4.09 (m, 2H), 4.34 (br s, 2H), 6.07 (d, 1H),6.67 (t, 1H), 7.49-7.94 (m, 3H), 8.82 (br s, 1H), 12.35 (br s, 1H). MSm/z 343 [M+H]+

Example 65-({4-[(1R,5S)-8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide

To a solution of5-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-N,3-dimethylpicolinamidehydrochloride (Preparation 1, 77 mg, 0.220 mmol) and triethylamine (133mg, 1.32 mmol) in DCM (10 mL) was added cyclopropanecarbonyl chloride(27 mg, 0.26 mmol) dropwise. The reaction was stirred at roomtemperature for 1 hour before concentrating in vacuo. The residue waspurified using preparative HPLC to afford the title compound (48 mg,52%).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.60-0.85 (m, 4H), 1.53-2.07 (m, 5H),2.56 (s, 3H), 2.75 (d, 3H), 2.95-3.04 (m, 1H), 3.04-3.15 (m, 1H),3.96-4.26 (m, 2H), 4.55-4.67 (m, 1H), 4.73-4.85 (m, 1H), 6.28-6.37 (m,1H), 7.99-8.11 (m, 2H), 8.39-8.47 (m, 1H), 8.74-8.81 (m, 1H), 9.52 (s,1H). MS m/z 444 [M+Na]⁺

Examples 7 and 8[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanoneand[(1R)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone

To a solution of (S)-2,2-difluorocyclopropane-1-carboxylic acid(Preparation 68, 318 mg, 2.61 mmol) in DCM (20 mL) was added4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19, 700 mg, 2.17 mmol), HATU (1.02 g, 2.61mmol and DIPEA (0.76 mL, 4.34 mmol) and the reaction was stirred at roomtemperature for 18 hours. The reaction was diluted with DCM andsaturated aqueous ammonium chloride solution. The organic layer wasseparated, washed with further ammonium chloride solution andconcentrated in vacuo. The residue was purified using silica gel columnchromatography eluting with 0-12% MeOH and 1% NH₄OH in DCM. The residuewas dissolved in DCM and further washed with saturated aqueous ammoniumchloride solution three times. The organic layer was collected,concentrated in vacuo and dried to afford the title compound (500 mg,60%).

The title compound and its enantiomer may also be prepared according tothe same method using racemic 2,2-difluorocyclopropane-1-carboxylic acidwith additional chiral separation of the enantiomers after purificationusing the method below to afford:

Peak 1: Example 7[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.58-2.06 (m, 6H), 2.82-3.27 (m, 3H),3.80 (s, 3H), 4.14 (br s, 2H), 4.55-4.74 (m, 2H), 6.07-6.19 (m, 1H),7.44 (s, 1H), 7.74 (br s, 1H), 7.93 (d, 1H), 8.90 (br s, 1H). MS m/z 390[M+H]⁺; [α]_(D) ²⁰ 50.1 (c 1.27, EtOH)

Peak 2: Example 8[(1R)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.58-2.06 (m, 6H), 2.82-3.27 (m, 3H),3.80 (s, 3H), 4.14 (br s, 2H), 4.55-4.74 (m, 2H), 6.07-6.19 (m, 1H),7.44 (s, 1H), 7.74 (br s, 1H), 7.93 (d, 1H), 8.90 (br s, 1H). MS m/z 390[M+H]⁺; [α]_(D) ²⁰ −51 (c 0.66, EtOH)

Example 7 may also be prepared according to the following method:

To a solution of (S)-2,2-difluorocyclopropane-1-carboxylic acid(Preparation 68, 18.1 g, 35.33 mmol),4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19, 11 g, 40 mmol) and DIPEA (41.7 mL, 246mmol) in DMF (60 mL) was added T3P (102 mL, 176 mmol) and the reactionwas stirred at room temperature for 1.5 hours. The reaction was quenchedby the addition of saturated aqueous NaHCO₃ solution until pH 6 andconcentrated in vacuo. The residue was dissolved in DCM and washed withsaturated aqueous NaHCO₃ solution followed by water. The organic layerwas collected, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified using silica gel column chromatography eluting with0-15% MeOH in DCM with 1% ammonia followed by chiral preparation usingChiral Tech OD-H 250 mm×21.2 mm, 5μ, using mobile phase A 75% CO₂ andmobile phase B 25% MeOH at a flow rate of 80 mL/min.

Example 94-({4-[8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-5-fluoropyrimidin-2-yl}amino)-N-ethylbenzamide

To a solution of4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoropyrimidin-2-yl)amino)-N-ethylbenzamidehydrochloride (Preparation 24, 50 mg, 0.14 mmol) in DCM (5 mL) was addedtriethylamine (0.1 mL, 0.7 mmol), HATU (50 mg, 0.135 mmol) andcyclopropanecarboxylic acid (15 mg, 0.17 mmol). The reaction was stirredat room temperature for 18 hours before purification directly usingsilica gel column chromatography eluting with 0-10% MeOH in DCM toafford the title compound. ¹H NMR (400 MHz, CDCl₃): δ ppm 0.78 (br s,2H), 1.00 (d, 2H), 1.21 (t, 3H), 1.61-1.75 (m, 1H), 1.79 (d, 1H),1.83-1.97 (m, 2H), 2.05 (d, 2H), 3.25 (dd, 2H) 3.36-3.53 (m, 2H), 4.16(d, 1H), 4.28 (d, 1H), 4.52 (d, 1H), 4.74 (br s, 1H), 6.28 (t, 1H), 7.37(s, 1H), 7.53 (d, 2H), 7.70 (d, 2H), 7.85 (d, 1H). MS m/z 439 [M+H]⁺

Example 103-chloro-5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N-methylpyridine-2-carboxamide

The title compound was prepared according to the method described forExample 9 using5-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-3-chloro-N-methylpicolinamidehydrochloride (Preparation 5) and(S)-2,2-difluorocyclopropane-1-carboxylic acid (Preparation 68). Theresidue was purified by preparative HPLC followed by chiralchromatography as described below:

Preparative HPLC: DIKMA Diamonsil(2) C18 200×20 mm×5 μm

Mobile phase: from 10% MeCN in water (0.225% formic acid) to 60% MeCN inwater (0.225% formic acid)

Preparative chiral chromatography: Chiralpak AD 250×30 mm I.D.10 μm

Mobile phase: Supercritical CO₂:MeOH (0.1% aqueous ammonia) 55:45;

Flow rate: 50 mL/min

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.61-2.03 (m, 6H), 2.75 (d, 3H),2.92-3.10 (m, 2H), 3.18-3.26 (m, 1H), 4.15 (br s, 2H), 4.58-4.76 (m,2H), 6.40 (dd, 1H), 8.05-8.14 (m, 1H), 8.44 (d, 2H), 8.81 (dd, 1H), 9.77(d, 1H). MS m/z 478 [M+H]⁺

Examples 11 and 12[(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-({6-[(2R)-1-hydroxypropan-2-yl]pyridin-3-yl}amino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanoneand(([(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-({6-[(2S)-1-hydroxypropan-2-yl]pyridin-3-yl}amino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone

The title compounds were prepared according to the method described byExample 9 using racemic2-(5-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)pyridin-2-yl)propan-1-olhydrochloride (Preparation 2) and(S)-2,2-difluorocyclopropane-1-carboxylic acid (Preparation 68). Theresidue was purified using preparative HPLC followed by enantiomericseparation using chiral chromatography as described below:

Preparative HPLC: Kromasil Eternity XT C18 250×21.2×10 μm

Mobile phase: from 16% MeCN in water (Ammonia pH=10) to 36% MeCN inwater (Ammonia pH=10);

Flow Rate: 30 mL/min

Preparative chiral chromatography: Chiralpak AD 250×30 mm I.D.10 μm

Mobile phase: Supercritical CO₂:IPA (aqueous ammonia) 55:45; Flow rate:70 mL/min

First eluting compound was arbitrarily assigned as: Example 11:

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.19 (d, 3H), 1.61-2.07 (m, 6H),2.83-3.06 (m, 3H), 3.24 (br s, 2H), 3.43-3.53 (m, 1H), 3.62 (m, 1H),4.18 (br s, 2H), 4.50-4.81 (m, 3H), 6.27 (m, 1H), 7.15 (d, 1H),7.93-8.11 (m, 2H), 8.74 (br s, 1H), 9.19 (s, 1H). MS m/z 445 [M+H]⁺

Second eluting compound was arbitrarily assigned as: Example 12

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.18 (d, 3H), 1.60-2.07 (m, 7H),2.83-3.04 (m, 3H), 3.25 (dd, 1H), 3.44-3.52 (m, 1H), 3.57-3.66 (m, 1H),4.13 (br s, 2H), 4.52-4.79 (m, 3H), 6.27 (dd, 1H), 7.15 (d, 1H),7.93-8.09 (m, 2H), 8.74 (d, 1H), 9.19 (s, 1H). MS m/z 445 [M+H]⁺

The following Examples were prepared according to the method describedfor Example 9 using the appropriate acid and amine as described.Purification details are as described or referred to below:

Example No. Structure/name Starting Materials Data 13 4-({4-[(1R,5S)-8-Cyanoacetic acid and 4- Rt = 1.76 minutes (cyanoacetyl)-3,8-((4-((1R,5S)-3,8- MS m/z 420 [M + H]⁺ diazabicyclo[3.2.1]oct-3-diazabicyclo[3.2.1]octan- Purification Method H.yl]pyrimidin-2-yl}amino)- 3-yl)pyrimidin-2- N-ethylbenzamideyl)amino)-N- ethylbenzamide hydrochloride (Preparation 4). 145-({4-[(1R,5S)-8- Cyclopropanecarboxylic ¹H NMR (400 MHz,(cyclopropylcarbonyl)- acid and 5-((4-((1R,5S)- MeOH-d₄): δ ppm 0.87-3,8- 3,8- 0.97 (m, 4H), 1.26 (t, diazabicyclo[3.2.1]oct-3-diazabicyclo[3.2.1]octan- 3H), 1.77-2.15 (m, 5H),yl]pyrimidin-2-yl}amino)- 3-yl)pyrimidin-2- 2.65 (s, 3H), 3.40 (m,N-ethyl-3-methylpyridine- yl)amino)-N-ethyl-3- 2H), 3.45 (m, 2H), 4.072-carboxamide methylpicolinamide (m, 1H), 4.56 (m, 1H), hydrochloride4.85 (m, 2H), 6.69 (d, (Preparation 3). 1H), 7.87 (br s, 1H), 7.90 (d,1H), 8.69 (br s, 1H). MS m/z 436 [M + H]⁺ PM A. 15 5-({4-[(1R,5S)-8-Cyclopropanecarboxylic ¹H NMR (400 MHz, (cyclopropylcarbonyl)- acid and5-((4-((1R,5S)- MeOH-d₄): δ ppm 0.86- 3,8- 3,8- 0.98 (m, 4H), 1.78-2.13diazabicyclo[3.2.1]oct-3- diazabicyclo[3.2.1]octan- (m, 5H), 2.62 (s,3H), yl]pyrimidin-2-yl}amino)- 3-yl)pyrimidin-2- 3.11-3.35 (m, 3H),4.41- 3-methylpyridine-2- yl)amino)-3- 4.49 (br s, 1H), 4.75-carboxamide methylpicolinamide 4.81 (m, 2H), 6.29-6.30 hydrochloride (m,1H), 8.00-8.01 (m, (Preparation 18). 2H), 8.75-8.76 (m, 1H). MS m/z 408[M + H]⁺ PM B. 16 cyclopropyl[(1R,5S)-3-(2- Cyclopropanecarboxylic ¹HNMR (400 MHz, {[1-(2-hydroxyethyl)-1H- acid and 2-(4-((4- MeOH-d₄): δppm 0.89- pyrazol-4- ((1R,5S)-3,8- 0.97 (m, 5H), 1.77-2.10yl]amino}pyrimidin-4-yl)- diazabicyclo- (m, 6H), 3.07-3.18 (m, 3,8-[3.2.1]octan-3- 2H), 3.87 (t, 2H), 4.19 (t, diazabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl)amino)- 2H), 4.72-4.77 (m, 2H), yl]methanone1H-pyrazol-1-yl)ethan-1- 6.12 (d, 1H), 7.52 (s, ol hydrochloride 1H),7.86-7.89 (m, 2H). (Preparation 20). MS m/z 384 [M + H]⁺ PM C. 171,2-oxazol-5-yl{(1R,5S)- 4-((1R,5S)-3,8- ¹H NMR (400 MHz,3-[2-(1H-pyrazol-4- diazabicyclo[3.2.1]octan- DMSO-d₆): δ ppm 1.56-ylamino)pyrimidin-4-yl]- 3-yl)- 2.39 (m, 4H), 2.96-3.22 3,8-N-(1l2-pyrazol-4- (m, 2H), 4.01-4.37 (m, diazabicyclo[3.2.1]oct-8-yl)pyrimidin-2-amine 2H), 4.61-4.96 (m, 2H), yl}methanone hydrochloride6.04-6.20 (m, 1H), 7.10 (Preparation 22) and (d, 1H), 7.42-7.84 (m,isoxazole-5-carboxylic 2H), 7.87-8.04 (m, 1H), acid. 8.77-8.82 (m, 1H),8.83- 8.94 (m, 1H), 12.19- 12.48 (m, 1H), MS m/z 367 [M + H]⁺ PM B. 18[(1R,5S)-3-(2-{[5-chloro- 2-(5-((4-((1R,5S)-3,8- ¹H NMR (400 MHz, 6-(2-diazabicyclo[3.2.1]octan- MeOH-d₄): δ ppm 1.75- hydroxyethyl)pyridin-3-3-yl)pyrimidin-2- 2.07 (m, 6H), 3.00-3.07 yl]amino}pyrimidin-4-yl)-yl)amino)-3- (m, 1H), 3.11 (s, 2H), 3,8- chloropyridin-2-yl)ethan-3.81-3.95 (m, 2H), 4.09- diazabicyclo[3.2.1]oct-8- 1-ol hydrochloride4.41 (m, 2H), 4.58-4.83 yl][(1S)-2,2- (Preparation 6) and (S)- (m, 4H),6.23-6.34 (m, difluorocyclopropyl]methanone 2,2- 1H), 7.92-8.06 (m, 1H),difluorocyclopropane-1- 8.24-8.35 (m, 1H), carboxylic acid 8.61-8.72 (m,1H). (Preparation 68). MS m/z 465 [M + H]⁺ PM D. 19 [(1S)-2,2-difluoro-2-(5-((4-((1R,5S)-3,8- ¹H NMR (400 MHz, cyclopropyl][(1R,5S)-diazabicyclo[3.2.1]octan- MeOH-d₄): δ ppm 1.58- 3-(2-{[5-fluoro-6-(2-3-yl)pyrimidin-2- 2.07 (m, 1H), 2.81-2.89 hydroxyethyl)pyridin-3-yl)amino)-3-fluoropyridin- (m, 1H), 2.90-3.26 (m,yl]amino}pyrimidin-4-yl)- 2-yl)ethan-1-ol 2H), 3.62-3.73 (m, 1H), 3,8-hydrochloride 3.98-4.32 (m, 1H), 4.53- diazabicyclo[3.2.1]oct-8-(Preparation 7) and (S)- 4.78 (m, 2H), 6.25-6.37 yl]methanone 2,2- (m,1H), 8.00-8.15 (m, difluorocyclopropane-1- 2H), 8.54-8.67 (m, 1H),carboxylic acid 9.46 (s, 1H). (Preparation 68). MS m/z 449 [M + H]⁺ PMD. 20 [(1S)-2,2-difluoro- (S)-1-(5-((4-((1R,5S)-3,8- ¹H NMR (400 MHz,cyclopropyl]{(1R,5S)- diazabicyclo[3.2.1]octan- DMSO-d₆): δ ppm 1.58-3-[2-({5-fluoro-6- 3-yl)pyrimidin-2- 2.07 (m, 1H), 2.81-2.89 [(3S)-3-yl)amino)-3-fluoropyridin- (m, 1H), 2.90-3.26 (m, hydroxypyrrolidin-1-2-yl)pyrrolidin-3-ol 2H), 3.62-3.73 (m, 1H), yl]pyridin-3- (Preparation8) and (S)- 3.98-4.32 (m, 1H), 4.53- yl}amino)pyrimidin-4-yl]-2,2-difluorocyclo- 4.78 (m, 2H), 6.25-6.37 3,8- propane-1-carboxylic (m,1H), 8.00-8.15 (m, diazabicyclo[3.2.1]oct-8- acid (Preparation 68). 2H),8.54-8.67 (m, 1H), yl}methanone 9.46 (s, 1H). MS m/z 490 [M + H]⁺ PM B.21 [(1S)-2,2-difluoro- (R)-1-(5-((4-((1R,5S)-3,8- ¹H NMR (400 MHz,cyclopropyl]{(1R,5S)- diazabicyclo[3.2.1]octan- DMSO-d₆): δ ppm 1.59-3-[2-({5-fluoro-6- 3-yl)pyrimidin-2- 2.06 (m, 8H), 2.82-3.03 [(3R)-3-yl)amino)-3-fluoropyridin- (m, 2H), 3.10-3.29 (m, hydroxypyrrolidin-1-2-yl)pyrrolidin-3-ol 2H), 3.48-3.67 (m, 3H), yl]pyridin-3- (Preparation9) and (S)- 4.00-4.37 (m, 3H), 4.59- yl}amino)pyrimidin-4-yl]-2,2-difluorocyclo- 4.74 (m, 2H), 4.85-4.94 3,8- propane-1-carboxylic (m,1H), 6.16-6.27 (m, diazabicyclo[3.2.1]oct-8- acid (Preparation 68). 1H),7.78-7.89 (m, 1H), yl}methanone 7.95 (s, 1H), 8.11-8.22 (m, 1H),8.90-9.03 (m, 1H). MS m/z 490 [M + H]⁺ PM B. 22 [(1S)-2,2-difluoro-1-(5-((4-((1R,5S)-3,8- ¹H NMR (400 MHz, cyclopropyl][(1R,5S)-diazabicyclo[3.2.1]octan- DMSO-d₆): δ ppm 1.70- 3-(2-{[5-fluoro-6-(3-3-yl)pyrimidin-2- 2.20 (m, 6H), 2.91-3.25 hydroxyazetidin-1-yl)amino)-3-fluoropyridin- (m, 3H), 3.81-3.93 (m, yl)pyridin-3-2-yl)azetidin-3-ol 2H), 4.08-4.24 (m, 1H), yl]amino}pyrimidin-4-yl)-(Preparation 10) and 4.24-4.38 (m, 3H), 4.53- 3,8-(S)-2,2-difluorocyclo- 4.79 (m, 5H), 6.14-6.26 diazabicyclo[3.2.1]oct-8-propane-1-carboxylic (m, 1H), 7.64-7.77 (m, yl]methanone acid(Preparation 68). 1H), 7.86-7.97 (m, 1H), 8.08-8.19 (m, 1H). MS m/z 476[M + H]⁺ PM D. 23 [(1R,5S)-3-(2-{[5-chloro- 2-((5-((4-((1R,5S)-3,8- ¹HNMR (400 MHz, 6-(2- diazabicyclo[3.2.1]octan- DMSO-d₆): δ ppm 1.61-hydroxyethoxy)pyridin-3- 3-yl)pyrimidin-2- 2.02 (m, 6H), 2.87-3.14yl]amino}pyrimidin-4-yl)- yl)amino)-3- (m, 2H), 3.21-3.29 (m, 3,8-chloropyridin-2- 1H), 3.67-3.77 (m, 1H), diazabicyclo[3.2.1]oct-8-yl)oxy)eth-an-1-ol 3.87-4.27 (m, 2H), 4.27- yl][(1S)-2,2- hydrochloride4.32 (m, 2H), 4.55-4.73 difluorocyclopropyl]methanone (Preparation 11)and (m, 2H), 4.79-4.88 (m, (S)-2,2- 1H), 6.21-6.32 (m, 1H),difluorocyclopropane-1- 7.94-8.05 (m, 1H), 8.22- carboxylic acid 8.41(m, 2H), 9.12-9.24 (Preparation 68). (m, 1H). MS m/z 481 [M + H]⁺ PM B.24 (1R,2R)-2-{[(1R,5S)-3-{2- (1R,2R)-2-cyanocyclo- ¹H NMR (400 MHz,[(1-ethyl-1H-pyrazol-4- propane-1-carboxylic DMSO-d₆): δ ppm 1.33yl)amino]pyrimidin-4-yl}- acid (Preparation 72) (t, 3H), 1.42 (m, 1H),3,8- and 4-((1R,5S)-3,8- 1.63-1.81 (m, 3H), 1.80-diazabicyclo[3.2.1]oct-8- diazabicyclo- 2.10 (m, 2H), 2.88-3.15yl]carbonyl}cyclopropane [3.2.1]octan-3-yl)-N-(1- (m, 4H), 4.07 (m, 2H),carbonitrile ethyl-1H-pyrazol-4- 4.04-4.09 (m, 2H), 4.60yl)pyrimidin-2-amine (s, 1H), 4.85 (s, 1H), hydrochloride 6.11 (m, 1H),7.45 (s, (Preparation 23). 1H), 7.75 (s, 1H), 7.92 (d, 1H), 8.86 (s,1H). MS m/z 393 [M + H]⁺ PM B (RT = 8.31 min). 25 [(1S)-2,2-(5-((4-((1R,5S)-3,8- ¹H NMR (400 MHz, difluorocyclopropyl][(1R,diazabicyclo[3.2.1]octan- DMSO-d₆): δ ppm 1.57- 5S)-3-(2-{[5-fluoro-6-3-yl)pyr-imidin-2-yl)amino)- 2.08 (m, 7H), 2.95 (d,(hydroxymethyl)pyridin- 3-fluoro-pyridin-2- 1H), 3.03 (d, 1H), 4.153-yl]amino}pyrimidin-4- yl)methanol (br s, 2H), 4.50 (s, 2H), yl)-3,8-hydrochloride 4.59-4.76 (m, 2H), 5.15 diazabicyclo[3.2.1]oct-8-(Preparation 12) and (br s, 1H), 6.34 (m, 1H), yl]methanone (S)-2,2-8.06 (d, 1H), 8.12 (d, difluorocyclopropane-1- 1H), 8.62 (d, 1H), 9.56carboxylic acid (br s, 1H). (Preparation 68). MS m/z 435 [M + H]⁺ PM B.26 2-[5-({4-[(1R,5S)-8- 2-(5-((4-((1R,5S)-3,8- ¹H NMR (400 MHz,{[(1S)-2,2- diazabicyclo[3.2.1]octan- DMSO-d₆): δ ppm 1.67-difluorocyclopropyl]carbonyl}- 3-yl)pyrimidin-2- 1.884 (m, 11H), 2.92-3,8- yl)amino)-pyridin-2-yl)-2- 2.95 (m, 2H), 3.20-3.28diazabicyclo[3.2.1]oct-3- methylprop-anenitrile (m, 2H), 4.20 (m, 2H),yl]pyrimidin-2- hydrochloride 4.65 (m, 2H), 6.29-6.32yl}amino)pyridin-2-yl]-2- (Preparation 13) and (m, 1H), 7.47-7.50 (m,methylpropanenitrile (S)-2,2- 1H), 8.01-8.03 (m, 1H),difluorocyclopropane-1- 8.24-8.26 (m, 1H), 8.81 carboxylic acid (br s,1H), 9.41 (s, 1H). (Preparation 68). MS m/z 454 [M + H]⁺ PM B. 275-({4-[(1R,5S)-8- 5-((4-((1R,5S)-3,8- ¹H NMR (400 MHz, {[(1R,2R)-2-diazabicyclo[3.2.1]octan- DMSO-d₆): δ ppm 1.35cyanocyclopropyl]carbonyl}- 3-yl)pyrimidin-2- (m, 2H), 1.65 (m, 1H),3,8- yl)amino)-3-fluoro-N- 1.75 (m, 2H), 2.09 (m,diazabicyclo[3.2.1]oct-3- methylpic-olinamide 2H), 2.76 (m, 3H), 2.94-yl]pyrimidin-2-yl}amino)- hydrochloride 3.08 (m, 3H), 4.15 (m,3-fluoro-N- (Preparation 14) and 2H), 4.61 (m, 1H), 4.88methylpyridine-2- (1R,2R)-2-cyanocyclo- (m, 1H), 6.40-6.43 (m,carboxamide propane-1-carboxylic 1H), 8.08-8.10 (m, 1H), acid(Preparation 72). 8.28 (m, 1H), 8.43-8.44 (m, 1H), 8.69 (s, 1H), 9.89(s, 1H). MS m/z 452 [M + H]⁺ PM B. 28 5-({4-[(1R,5S)-8-{[(1R)- Racemic2,2-difluoro- ¹H NMR (400 MHz, 2,2- cyclopropane-1- DMSO-d₆): δ ppm1.60- difluorocyclopropyl]carbonyl}- carboxylic acid and 5-((4- 2.00 (m,6H), 2.75-2.76 3,8- ((1R,5S)-3,8- (m, 3H), 2.95-3.05 (m,diazabicyclo[3.2.1]oct-3- diazabicyclo[3.2.1]octan- 2H), 3.25 (m, 1H),4.20 yl]pyrimidin-2-yl}amino)- 3-yl)pyrimidin-2-yl)amino)- (m, 2H), 4.65(m, 2H), 3-fluoro-N- 3-fluoro-N-methyl- 6.40 (m, 1H), 8.09-8.11methylpyridine-2- picolinamide hydrochloride (m, 1H), 8.20-8.30 (m,carboxamide (Preparation 14) with 1H), 8.40 (m, 1H), 8.69 separation ofthe (s, 1H), 9.89 (s, 1H). enantiomers as SFC Rt = 5.05 minutesdescribed above in PM E. 29 5-({4-[(1R,5S)-8-{[(1S)- Racemic2,2-difluoro- ¹H NMR (400 MHz, 2,2- cyclopropane-1- DMSO-d₆): δ ppm1.60- difluorocyclopropyl]carbonyl}- carboxylic acid and 5-((4- 2.05 (m,6H), 2.75-2.76 3,8- ((1R,5S)-3,8- (m, 3H), 2.95-2.98 (m,diazabicyclo[3.2.1]oct-3- diazabicyclo[3.2.1]octan- 2H), 3.19 (m, 1H),4.20 yl]pyrimidin-2-yl}amino)- 3-yl)pyrimidin-2-yl)amino)- (m, 2H),4.63-4.73 (m, 3-fluoro-N- 3-fluoro-N-methylpicol- 1H), 6.39-6.43 (m,1H), methylpyridine-2- inamide hydrochloride 8.09-8.11 (m, 1H), 8.24-carboxamide (Preparation 14) with 8.27 (m, 1H), 8.43 (m, separation ofthe 1H), 8.69 (s, 1H), 9.89 enantiomers as (s, 1H). described above inPM MS m/z 462 [M + H]⁺ E. SFC Rt = 5.51 minutes 303-chloro-5-({4-[(1R,5S)- 5-((4-((1R,5S)-3,8- ¹H NMR (400 MHz,8-(cyclopropylcarbonyl)- diazabicyclo[3.2.1]octan- DMSO-d₆): δ ppm 0.783,8- 3-yl)pyrimidin-2-yl)amino)- (d, 4H), 1.57-1.89 (m,diazabicyclo[3.2.1]oct-3- 3-chloro-N-methylpicol- 3H), 2.03 (br s, 2H),yl]pyrimidin-2-yl}amino)- inamide hydrochloride 2.76 (d, 3H), 3.00-3.16N-methylpyridine-2- (Preparation 5) and (m, 2H), 4.05 (s, 2H),carboxamide cyclopropanecarboxylic 4.62 (br s, 1H), 4.79 (br acid. s,1H), 6.39 (d, 1H), 8.08 (d, 1H), 8.45 (s, 2H), 8.82 (d, 1H), 9.77 (s,1H). MS m/z 442 [M + H]⁺ PM B. 31 3-chloro-5-({4-[(1R,5S)-5-((4-((1R,5S)-3,8- ¹H NMR (400 MHz, 8-{[(1R,2R)-2-diazabicyclo[3.2.1]octan- DMSO-d₆): δ ppm 1.21cyanocyclopropyl]carbonyl}- 3-yl)pyrimidin-2- (t, 1H), 1.30-1.47 (m,3,8- yl)amino)-3-chloro-N- 2H), 1.64 (d, 1H), 1.68-diazabicyclo[3.2.1]oct-3- methylpicol-inamide 1.88 (m, 2H), 1.90-2.14yl]pyrimidin-2-yl}amino)- hydrochloride (m, 2H), 2.73 (d, 3H),N-methylpyridine-2- (Preparation 5) and 2.84-2.96 (m, 1H), carboxamide(1R,2R)-2- 2.97-3.22 (m, 2H), 4.12 cyanocyclopropane-1- (br s, 2H), 4.60(d, 1H), carboxylic acid 4.87 (br s, 1H), 6.39 (t, (Preparation 72).1H), 8.07 (dd, 1H), 8.43 (br s, 2H), 8.80 (d, 1H), 9.77 (s, 1H). MS m/z467 [M + H]⁺ PM B. 32 5-({4-[(1R,5S)-8- 5-((4-((1R,5S)-3,8- ¹H NMR (400MHz, {[(1R,2R)-2- diazabicyclo[3.2.1]octan- DMSO-d₆): δ ppm 1.29-cyanocyclopropyl]carbonyl}- 3-yl)pyrimidin-2- 1.51 (m, 2H), 1.55-2.163,8- yl)amino)-N,3- (m, 5H), 2.56 (s, 3H), diazabicyclo[3.2.1]oct-3-dimethylpicolinamide 2.75 (d, 3H), 2.89-3.12 yl]pyrimidin-2-yl}amino)-hydrochloride (m, 3H), 4.13 (br s, 2H), N,3-dimethylpyridine-2-(Preparation 1) and 4.61 (d, 1H), 4.89 (br s, carboxamide(1R,2R)-2-cyanocyclo- 1H), 6.35 (t, 1H), 8.02- propane-1-carboxylic 8.10(m, 2H), 8.45 (d, acid (Preparation 72). 1H), 8.77 (s, 1H), 9.56 (s,1H). MS m/z 447 [M + H]⁺ PM B. 33 5-((4-((1R,5S)-8-((S)-2,2-5-((4-((1R,5S)-3,8- ¹H NMR (400 MHz, difluorocyclopropane-1-diazabicyclo[3.2.1]octan- DMSO-d₆): δ ppm 1.67- carbonyl)-3,8-3-yl)pyrimidin-2- 1.88 (m, 6H), 2.57 (d, diazabicyclo[3.2.1]octan-yl)amino)-N,3- 3H), 2.76 (d, 3H), 2.95- 3-yl)pyrimidin-2-dimethylpicolinamide 3.06 (m, 2H), 3.21-3.24 yl)amino)-N,3-hydrochloride (m, 1H), 4.64-4.72 (m, dimethylpicolinamide(Preparation 1) and 2H), 6.32-6.36 (m, 1H), racemic 2,2- 8.064 (d, 2H),8.43 (s, difluorocyclopropane-1- 1H), 8.77 (d, 1H), 9.54 carboxylic acidwith (s, 1H). separation of the isomers MS m/z 458 [M + H]⁺ using PM DPeak 2 arbitrarily assign as title compound. 34 5-[(4-{(1R,5S)-8-[(2,2-Racemic 2,2-difluoro- ¹H NMR (400 MHz, difluorocyclopropyl)carbonyl]-cyclopropane-1- DMSO-d₆): δ ppm 1.85- 3,8- carboxylic acid and 5-((4-2.03 (m, 6H), 2.57 (s, diazabicyclo[3.2.1]oct-3- ((1R,5S)-3,8- 3H), 2.98(d, 1 H), 3.07- yl}pyrimidin-2-yl)amino]- diazabicyclo[3.2.1]octan- 3.28(m, 3H), 4.08-4.36 3-methylpyridine-2- 3-yl)pyrimidin-2-yl)amino)- (m,2H), 4.62-4.75 (m, carboxamide 3-methylpicolinamide 2H), 6.34-6.38 (m,1H), hydrochloride 7.20 (s, 1H), 7.84 (s, (Preparation 26). 1H),8.07-8.10 (m, 2H), 8.74-8.78 (m, 1H), 9.54 (s, 1H). MS m/z 444 [M + H]⁺PM B. 35 5-({4-[(1R,5S)-8-{[(1S)- (S)-2,2-difluorocyclo- ¹H NMR (400MHz, 2,2- propane-1-carboxylic DMSO-d₆): δ ppm 1.85-difluorocyclopropyl]carbonyl}- acid (Preparation 70) 2.03 (m, 6H), 2.57(s, 3,8- and 5-((4-((1R,5S)-3,8- 3H), 2.98 (d, 1 H), 3.07-diazabicyclo[3.2.1]oct-3- diazabicyclo[3.2.1]octan- 3.28 (m, 3H),4.08-4.36 yl]pyrimidin-2-yl}amino)- 3-yl)pyrimidin-2- (m, 2H), 4.62-4.75(m, 3-methylpyridine-2- yl)amino)-3- 2H), 6.34-6.38 (m, 1H), carboxamidemethylpicolinamide 7.20 (s, 1H), 7.84 (s, hydrochloride 1H), 8.07-8.10(m, 2H), (Preparation 26). 8.74-8.78 (m, 1H), 9.54 (s, 1H). Rt = 0.55minutes; MS m/z 444 [M + H]⁺ PM F. 36 cyclopropyl[(1R,5S)-3-{2-4-((1R,5S)-3,8- ¹H NMR (400 MHz, [(1-methyl-1H-pyrazol-4-diazabicyclo[3.2.1]octan- CDCl₃): δ ppm 0.78 (m,yl)amino]pyrimidin-4-yl}- 3-yl)-N-(1-methyl-1H-pyrazol- 4H), 0.90-1.00(m, 2H), 3,8- 4-yl)pyrimidin-2-amine 1.60-2.05 (m, 4H), 3.10diazabicyclo[3.2.1]oct-8- hydrochloride (m, 1H), 3.80 (s, 1H),yl]methanone (Preparation 26) and 3.90 (m, 1H), 4.10 (m,Cyclopropylcarboxylic 1H), 4.50 (m, 1H), 4.80 acid. (m, 1H), 5.80 (d,1H), 7.20 (d, 1H), 7.40 (s, 1H), 7.60 (br s, 1H), 7.90 (m, 1H). Rt =0.59 minutes MS m/z 354 [M + H]⁺ PM F. 37 (1S,2R)-2-{[(1R,5S)-3-{2-4-((1R,5S)-3,8- ¹H NMR (400 MHz, [(1-methyl-1H-pyrazol-4-diazabicyclo[3.2.1]octan- MeOH-d₄): δ ppm 1.40-yl)amino]pyrimidin-4-yl}- 3-yl)-N-(1-methyl-1H-pyrazol- 1.50 (m, 1H),1.70-2.20 3,8- 4-yl)pyrimidin-2-amine (m, 6H), 2.60-2.70 (m,diazabicyclo[3.2.1]oct-8- hydrochloride 1H), 3.10-3.30 (m, 2H),yl]carbonyl}cyclopropane- (Preparation 19) and 3.35 (s, 3H), 4.10-4.40carbonitrile (1S,2R)-2- (br m, 2H), 4.80 (m, 2H), cyanocyclopropane-1-6.70 (m, 1H), 7.55 (s, carboxylic acid (J. Med. 1H), 7.80 (s, 1H), 7.90Chem. (2013), 56 (11), (m, 1H). 4521-4536). LCMS Rt = 0.50 minutes MSm/z 379 [M + H]⁺ PM F. 38 (1R,2S)-2-{[(1R,5S)-3-{2- 4-((1R,5S)-3,8- ¹HNMR (400 MHz, [(1-methyl-1H-pyrazol-4- diazabicyclo[3.2.1]octan-MeOH-d₄): δ ppm 1.40- yl)amino]pyrimidin-4-yl}-3-yl)-N-(1-methyl-1H-pyrazol-4- 1.50 (m, 1H), 1.70-2.20 3,8-yl)pyrimidin-2-amine (m, 6H), 2.60-2.70 (m, diazabicyclo[3.2.1]oct-8-hydrochloride 1H), 3.10-3.30 (m, 2H), yl]carbonyl}cyclopropane-(Preparation 19) and 3.35 (s, 3H), 4.10-4.40 carbonitrile (1R,2S)-2- (brm, 2H), 4.80 (m, 2H), cyanocyclopropane-1- 6.70 (m, 1H), 7.55 (s,carboxylic acid (J. Med. 1H), 7.80 (s, 1H), 7.90 Chem. (2013), 56 (11),(m, 1H). 4521-4536). LCMS Rt = 0.49 minutes MS m/z 379 [M + H]⁺ PM F. 39(3,3- 4-((1R,5S)-3,8- ¹H NMR (400 MHz, difluorocyclobutyl)[(1R,5S)-diazabicyclo[3.2.1]octan- CDCl₃): δ ppm 1.70- 3-{2-[(1-methyl-1H-3-yl)-N-(1-methyl-1H-pyrazol-4- 2.00 (m, 4H), 2.70-3.00 pyrazol-4-yl)pyrimidin-2-amine (m, 4H), 3.00-3.18 (m, yl)amino]pyrimidin-4-yl}-hydrochloride 2H), 3.25-3.40 (m, 2H), 3,8- (Preparation 19) and 3.80 (s,3H), 4.05-4.35 diazabicyclo[3.2.1]oct-8- 3,3-difluoro- (br m, 2H), 4.40(m, 1H), yl]methanone cyclobutanecarboxylic 4.75 (m, 1H), 6.10 (m, acid.1H), 7.50 (m, 1H), 7.75 (m, 1H), 7.90 (m, 1H). LCMS Rt = 0.65 minutes MSm/z 404 [M + H]⁺ PM F. 40 4-({4-[(1R,5S)-8-{[(1S)-2,2-4-((4-((1R,5S)-3,8- Rt = 2.43 minutes MS difluorocyclopropyl]carbonyl}-diazabicyclo[3.2.1]octan- m/z 458 [M + H]⁺ 3,8- 3-yl)pyrimidin-2- PM G.diazabicyclo[3.2.1]oct-3- yl)amino)-N,6- yl]pyrimidin-2-yl}amino)-dimethylpicolinamide N,6-dimethylpyridine-2- (Preparation 16) andcarboxamide (S)-2,2- difluorocyclopropane-1- carboxylic acid(Preparation 68). 41 4-({4-[(1R,5S)-8-{[(1S)- 4-((4-((1R,5S)-3,8- Rt =1.59 minutes MS 2,2- diazabicyclo[3.2.1]octan- m/z 474 [M + H]⁺difluorocyclopropyl]carbonyl}- 3-yl)pyrimidin-2- PM G. 3,8- yl)amino)-6-diazabicyclo[3.2.1]oct-3- (hydroxymethyl)-N- yl]pyrimidin-2-yl}amino)-methylpicolinamide 6-(hydroxymethyl)-N- hydrochloride methylpyridine-2-(Preparation 17) and carboxamide (S)-2,2- difluorocyclopropane-1-carboxylic acid (Preparation 68).

Examples 42 and 43[(1R,2R)-2-fluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanoneand[(1S,2S)-2-fluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone

The title compounds were prepared according to the method described forExample 9 using4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19) and cis-racemic(1S,2S)-2-fluorocyclopropane-1-carboxylic acid (PCT Publication No.WO2005095322). The cis-racemic title compound was separated into itsenantiomers using chiral chromatography as described below:

Column: IB 21 mm×250 mm×5 μm, Mobile phase A: CO₂; Mobile phase B: 0.2%Ammonium hydroxide in MeOH; 80:20 A/B; 15 minutes hold; flow rate 65mL/min.

¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.10-1.20 (m, 1H), 1.70-2.30 (m, 6H),3.10-3.25 (m, 3H), 3.85 (s, 3H), 4.10-4.40 (br m, 2H), 4.75-5.00 (m,2H), 6.15 (m, 1H), 7.55 (s, 1H), 7.80 (m, 1H), 7.90 (m, 1H). LCMSRt=0.50 minutes; MS m/z 372 [M+H]⁺

Examples 44 and 455-({4-[(1R,5S)-8-{[(1R,2S)-2-fluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]perimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamideand5-({4-[(1R,5S)-8-{[(1S,2R)-2-fluorocyclopropyl]carbonyl}-3,8-diazabicclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide

The title compounds were prepared according to the method described forExample 9 using5-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-N,3-dimethylpicolinamidehydrochloride (Preparation 1) and trans-racemic(1S,2S)-2-fluorocyclopropane-1-carboxylic acid (PCT Publication No.WO2005095322). The trans-racemic title compound was separated into itsenantiomers using chiral chromatography as described below:

Column: Lux-cellulose-3; 250 mm×21.2 mm, 5μ; Mobile phase A: 75% CO₂,mobile phase B: MeOH, flow rate 80 mL/min.

First eluting isomer: Rt=6.06 minutes; Second eluting isomer: Rt=6.40minutes

¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.30-1.40 (m, 1H), 1.40-1.60 (m, 1H),1.80-1.90 (m, 1H), 1.90-2.05 (m, 1H), 2.10-2.40 (m, 1H), 2.50-2.60 (m,1H), 3.10-3.40 (m, 4H), 4.10-4.40 (br m, 2H), 4.70-5.00 (m, 2H), 6.30(m, 1H), 8.00 (m, 2H), 8.80 (br s, 1H). MS m/z 440 [M+H]⁺

Example 46(1-fluorocyclopropyl)[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone

To a solution of4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19,100 mg, 0.311 mmol) in dioxane (10 mL) wasadded DIEA (401 mg, 3.11 mmol) and racemic4-chlorophenyl-1-fluorocyclopropane-1-carboxylate (Eur. Pat. Appl.533013, 80 mg, 0.373 mmol). The reaction mixture was heated to refluxfor 18 hours. The reaction was concentrated in vacuo and purified usingpreparative HPLC to afford the title compound as a yellow solid as thehemiformate salt (37 mg, 32%).

Preparative HPLC using Phenomenex Synergi C18 150 mm×30 mm×4 μm; from 5%MeCN in water (0.225% FA) to 25% MeCN in water (0.225% FA). ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.27-1.32 (m, 4H), 1.69 (m, 2H), 1.90 (m, 2H),3.04-3.07 (m, 2H), 3.18 (s, 3H), 4.13 (m, 2H), 4.72 (m, 2H), 6.11 (d,1H), 7.42 (s, 1H), 7.92 (d, 1H), 8.87 (s, 1H). MS m/z 372 [M+H]⁺

Example 47(1R,5S)-N-(2-cyanoethyl)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

To a solution of4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19, 50 mg, 0.175 mmol) in DCM (10 mL) wasadded triethylamine (53 mg, 0.525 mmol) andN-(2-cyanoethyl)-1H-imidazole-1-carboxamide (Preparation 78, 0.35 mmol)and the reaction was stirred at room temperature for 3 hours. Thereaction was concentrated in vacuo and purified using preparative HPLC(Purification Method B) to afford the title compound (31 mg, 47%). ¹HNMR (400 MHz, DMSO-d₆): δ ppm 1.59-1.61 (m, 2H), 1.80-1.82 (m, 2H), 2.66(t, 2H), 3.02 (m, 4H), 3.28-3.29 (m, 2H), 3.78 (s, 3H), 3.97 (br s, 2H),4.36 (s, 2H), 6.10 (d, 1H), 7.14 (m, 1H), 7.43 (s, 1H), 7.72 (s, 1H),7.90 (d, 1H), 8.84 (s, 1H). MS m/z 382 [M+H]⁺

Example 48(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-N-[5-(trifluoromethyl)pyridin-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared according to the method described forExample 47 using phenyl[4-(trifluoromethyl)pyridine-2-yl]carbamate (PCTPublication No. WO2010006938) at 50° C. and purified using preparativeHPLC (Purification Method B). ¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.80-1.83(m, 2H), 2.02 (m, 2H), 3.20-3.23 (m, 2H), 3.85 (s, 3H), 4.17 (br m, 2H),4.64 (m, 2H), 6.14 (d, 1H), 7.51 (s, 1H), 7.75 (s, 1H), 7.87 (d, 1H),7.95-7.98 (m, 1H), 8.08 (d, 1H), 8.54 (s, 1H). MS m/z 474 [M+H]⁺

Example 49cyclopropyl{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone

To a solution of((1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclo-propyl)methanone(Preparation 28, 100 mg, 0.342 mmol) and 1-H-pyrazol-4-amine (100 mg,0.54 mmol) in iPrOH (5 mL) was added cHCl (2 drops) and the reaction washeated to 140° C. under microwave irradiation for 1 hour. The reactionwas cooled, concentrated in vacuo and purified by silica gel columnchromatography eluting with 5% MeOH in DCM followed by preparative HPLC(Purification Method B) to afford the title compound (34 mg, 29%).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.77 (br s, 4H), 1.63 (br s, 1H), 1.74(br s, 2H), 2.01 (d, 2H), 2.94-3.10 (m, 2H), 3.87-4.27 (m, 2H),4.53-4.84 (m, 2H), 6.10 (d, 1H), 7.53 (br s, 1H), 7.78 (br s, 1H), 7.92(d, 1H), 8.86 (br s, 1H), 12.36 (br s, 1H). MS m/z 340 [M+H]⁺

Example 50 and 51((1R,5S)-3-(2-((1H-Pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((R)-2,2-difluorocyclopropyl)methanoneand((1R,5S)-3-(2-((1H-Pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((S)-2,2-difluorocvclopropyl)methanone

The title compounds were prepared according to the method described forExample 49 using racemic((1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(2,2-difluorocyclopropyl)-methanone(Preparation 30) and tert-butyl 4-amino-1H-pyrazole-1-carboxylate. Theenantiomers were purified using preparative HPLC (Purification Method B)followed by separation using chiral chromatography: Chiral preparativeHPLC: Column AD 250 mm×30 mm I.D. 20 μm; Mobile phase: supercriticalCO₂/MeOH (0.05% ammonia, 55/45 at 80 mL/min.

Example 50:((1R,5S)-3-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabi-cyclo[3.2.1]octan-8-yl)((R)-2,2-difluorocyclopropyl)methanone(25 mg, 11%)

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.60-2.04 (m, 5H), 2.84-2.96 (m, 1H),2.96-3.17 (m, 1H), 3.18-3.32 (m, 2H), 3.97-4.40 (m, 2H), 4.54-4.76 (m,2H), 6.05-6.22 (m, 1H), 7.43-7.86 (m, 2H), 7.89-8.01 (m, 1H), 8.84-9.05(m, 1H), 12.32-12.51 (m, 1H). MS m/z 376 [M+H]⁺

Example 51:((1R,5S)-3-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((S)-2,2-difluorocyclopropyl)methanone(23 mg, 10%)

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.59-2.05 (m, 5H), 2.86-2.95 (m, 1H),2.96-3.16 (m, 1H), 3.16-3.32 (m, 2H), 3.93-4.40 (m, 2H), 4.54-4.77 (m,2H), 6.04-6.21 (m, 1H), 7.41-7.86 (m, 2H), 7.87-8.00 (m, 1H), 8.79-9.00(m, 1H), 12.27-12.43 (m, 1H). MS m/z 376 [M+H]⁺

Example 51 may also be prepared according to the following method:

To a solution of (S)-2,2-difluorocyclopropane-1-carboxylic acid(Preparation 68, 28 mg, 0.227 mmol),4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1I2-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 22, 56 mg, 0.21 mmol) and DIPEA (0.22 mL,1.24 mmol) in dichloromethane (3 mL) and DMF (1 mL) was added HATU (97mg, 0.25 mmol) and the reaction was stirred at room temperature for 18hours. The reaction was concentrated in vacuo. The residue was purifiedusing silica gel column chromatography eluting with 0-20% MeOH in DCM toafford the title compound (26 mg, 34%).

Example 52cyclopropyl{(1R,5S)-3-[2-(1,2-thiazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone

The title compound was prepared according to the method described forExample 49 using 4-isothiasolamine.

Preparative HPLC: Column: Phenomenex Gemini C18 250×21.2 mm×8 μm

Mobile phase: from 3% MeCN in water (0.225% formic acid) to 23% MeCN inwater (0.225% formic acid);

Flow Rate: 30 mL/min. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.70-0.77 (m,4H), 1.61-1.81 (m, 3H), 1.99-2.00 (m, 2H), 2.97-3.00 (m, 1H), 3.07-3.10(m, 1H), 4.11 (s, 2H), 4.62 (s, 1H), 4.77 (s, 1H), 6.24 (d, 1H), 8.00(d, 1H), 8.59 (s, 1H), 8.76 (s, 1H), 9.71 (s, 1H). MS m/z 357 [M+H]⁺

Example 53N,3-dimethyl-5-({4-[(1R,5S)-8-(1,2-oxazol-5-ylmethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)pyridine-2-carboxamide

To a solution of N-(2,2,2-trifluoroethyl)-1H-imidazole-1-carboxamide(Preparation 82) and5-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-N,3-dimethylpicolinamidehydrochloride (Preparation 1, 50 mg, 0.12 mmol) and5-isoxazolecarboxaldehyde (32 mg, 0.33 mmol) in MeCN (1 mL) was addedsodium triacetoxyborohydride (76 mg, 0.35 mmol) and the reaction wasstirred at room temperature for 1.5 hours. The reaction was quenched bythe addition of saturated aqueous NaHCO₃ solution and extracted intoEtOAc three times. The organic layer was collected, dried over magnesiumsulfate and concentrated in vacuo. The residue was purified by silicagel column chromatography eluting with 0-10% MeOH in DCM followed bytrituration with diethylether to afford the title compound (30 mg, 59%).LCMS Rt=0.69 minutes; MS m/z 435 [M+H]⁺

Example 54N,3-dimethyl-5-[(4-{(1R,5S)-8-[(3-methyloxetan-3-yl)methyl]-3,8-diazabicclo[3.2.1]oct-3-yl}pyrimidin-2-yl)amino]pyridine-2-carboxamide

The title compound may be prepared according to the method described forExample 53 using 3-methyloxetane-3-carbaldehyde with DIPEA in THF/DMSO.Purified using preparative HPLC.

Preparative HPLC: DIKMA Diamonsil(2) C18 200×20 mm×5 μm

Mobile phase: from 0-27% MeCN in water (0.225% FA); 35 mL/min flow rate.Rt=1.95 minutes; MS m/z 438 [M+H]⁺

Example 55N-(1-methyl-1H-pyrazol-4-yl)-4-[(1R,5S)-8-(1,2-thiazol-5-ylmethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-amine

To a solution of4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19, 100 mg, 0.351 mmol) and5-isothiazolecarboxaldehyde (55 mg, 0.49 mmol) in MeOH (10 mL) was addedtriethylamine (71 mg, 0.70 mmol) and acetic acid (3 drops). The solutionwas stirred at room temperature for 3 hours before the addition ofsodium cyanoborohydride (44 mg, 0.702 mmol) at 0° C. The reaction wasstirred at room temperature for 18 hours. The solution was concentratedin vacuo and purified by preparative HPLC (Purification Method B) toafford the title compound (26.2 mg, 20%). ¹H NMR (400 MHz, DMSO-d₆): δppm 1.57 (d, 2H), 1.96 (br s, 2H), 3.06 (d, 2H), 3.77 (s, 9H), 6.06 (d,1H), 7.28 (s, 1H), 7.42 (s, 1H), 7.74 (br s, 1H), 7.90 (d, 1H), 8.49 (d,1H), 8.83 (br s, 1H). MS m/z 383 [M+H]⁺

The following Examples were prepared according to the method describedfor Example 55 using4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19) and the appropriate aldehyde or ketone.Where necessary the imine formation was carried out at elevatedtemperatures of 95° C. in toluene with camphorsulfonic acid, ortriethylamine and acetic acid were omitted. Purification methods are asdescribed or referred to below:

Example No. Name SM/Data 56 N-(1-methyl-1H-pyrazol-5-isoxazolecarboxaldehyde 4-yl)-4-[(1R,5S)-8-(1,2- ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.54 (d, 2H), oxazol-5-ylmethyl)-3,8- 1.91-2.03 (m, 2H),3.03 (d, 2H), 3.66-4.05 (m, 7H), diazabicyclo[3.2.1]oct-3- 6.05 (d, 1H),6.47 (s, 1H), 7.41 (s, 1H), 7.72 (br s, yl]pyrimidin-2-amine 1H), 7.88(d, 1H), 8.52 (d, 1H), 8.83 (br s, 1H). MS m/z 337 [M + H]⁺ PM B. 57N-(1-methyl-1H-pyrazol- 2-thiazolecarboxaldehyde4-yl)-4-[(1R,5S)-8-(1,3- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.57 (d, 2H),thiazol-2-ylmethyl)-3,8- 1.90-2.03 (m, 2H), 3.06 (d, 2H), 3.41 (br s,2H), 3.76 diazabicyclo[3.2.1]oct-3- (s, 3H), 3.84-4.15 (m, 4H), 6.06 (d,1H), 7.41 (s, yl]pyrimidin-2-amine 1H), 7.64 (d, 1H), 7.74 (d, 2H), 7.89(d, 1H), 8.83 (br s, 1H). MS m/z 383 [M + H]⁺ PM B. 58N-(1-methyl-1H-pyrazol- 4-isoxazolecarboxaldehyde4-yl)-4-[(1R,5S)-8-(1,2- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.52 (d, 2H),oxazol-4-ylmethyl)-3,8- 1.96 (d, 2H), 3.02 (d, 2H), 3.43-3.47 (m, 4H),3.76 diazabicyclo[3.2.1]oct-3- (s, 5H), 6.03 (d, 1H), 7.41 (s, 1H), 7.72(br s, 1H), yl]pyrimidin-2-amine 7.87 (d, 1H), 8.02 (s, 1H), 8.31 (s,1H), 8.78 (br s, 1H). MS m/z 367 [M + H]⁺ PM B. 59 Cis and trans3-[(1R,5S)- 3-oxo-cyclobutanecarbonitrile and isolated as the3-{2-[(1-methyl-1H- cis/trans mixture. pyrazol-4- LCMS Rt = 0.63 minutesMS m/z 365 [M + H]⁺ yl)amino]pyrimidin-4-yl}- ¹H NMR (400 MHz, MeOH-d₄):δ ppm 1.70 (m, 2H), 3,8- 1.90 (m, 2H), 2.35 (m, 1H), 2.40 (m, 1H), 2.50(m, diazabicyclo[3.2.1]oct-8- 1H), 2.60 (m, 1H), 3.00 (m, 1H), 3.10-3.20(m, 3H), yl]cyclobutanecarbonitrile 3.25-3.45 (m, 5H), 4.00-4.15 (br m,2H), 6.10 (m, 1H), 7.55 (d, 1H), 7.80 (s, 1H), 7.90 (d, 1H).

Example 60N-(1-methyl-1H-pyrazol-4-yl)-4-{(1R,5S)-8-[1-(methylsulfonyl)azetidin-3-yl]-3,8-diazabicyclo[3.2.1]oct-3-yl}pyrimidin-2-amine

To a solution of tert-butyl3-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)azetidine-1-carboxylate(Preparation 135, 51 mg, 0.12 mmol) in DCM (1 mL) was added 4N HCl indioxane (2 mL) and the reaction was stirred at room temperature for 2hours. The reaction was concentrated in vacuo and dissolved in DCM (1mL). DIPEA (61 μl, 0.348 mmol) followed by methanesulfonyl chloride (10μl, 0.128 mmol) and the reaction was stirred at room temperature for 30minutes. The reaction was quenched by the addition of water,concentrated in vacuo and purified using silica gel columnchromatography eluting with 0-10% MeOH (1% ammonia) in DCM followed bypreparative HPLC (Purification Method H). Rt=1.18 minutes; MS m/z 419[M+H]⁺

Examples 61 and 625-({4-[(1R,5S)-8-(cis-3-cyanocyclobutyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamideand5-({4-[(1R,5S)-8-(trans-3-cyanocyclobutyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide

The title compounds were prepared using the method described for Example55 using 3-oxo-cyclobutanecarbonitrile and5-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-N,3-dimethylpicolinamidehydrochloride (Preparation 1). The isomers were separated using chiralchromatography as described below:

Column: Lux Cellulose-4 250 mm×21.2 mm×5 μm; Mobile phase A: Heptanes;Mobile phase B: Ethanol; from 50:50 A:B to 100% B at 10 minutes thenback to 50:50 A:B at 12.5 minutes. Flow rate: 27.0 mL/min. First elutingcompound was arbitrarily assigned as Example 61: Rt=8.45 minutes, MS m/z433 [M+H]⁺ Second eluting isomer was arbitrarily assigned as Example 62:Rt=9.35 minutes, MS m/z 433 [M+H]⁺

Examples 63 and 644-[(1R,5S)-8-{[(1R)-2,2-difluorocyclopropyl]methyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amineand4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]methyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

To a solution of4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19, 32 mg, 11 mmol) and racemic(2,2-difluorocyclopropyl)methyl 4-methylbenzenesulfonate (PCTPublication No. WO20130908375, 30 mg, 12 mmol) in MeCN (3 mL) was addedsodium carbonate (18 mg, 17 mmol) and tert-butylammonium iodide (6 mg,17 mmol) and the reaction was stirred at 60° C. for 42 hours. Thereaction was cooled and concentrated in vacuo. The residue waspartitioned between DCM and saturated aqueous ammonium chloridesolution. The organic layer was collected and purified using silica gelcolumn chromatography eluting with 0-10% MeOH (1% ammonia) in DCM. Theresidue was dissolved in DCM and washed with ammonium chloride threetimes before concentrating in vacuo. The residue was then dissolved inEtOAc and washed with saturated aqueous NaHCO₃ solution, water, brine,and concentrated in vacuo to afford the racemic title compound that wasseparated into the two enantiomers using chiral chromatography asdescribed below: Column: OJ-H 21 mm×250 mm×5μ, Mobile phase A: CO₂;Mobile phase B: MeOH (0.2% ammonium hydroxide) using 90% A and 10% B,Hold for 10 minutes, flow rate 75 mL/min.

¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.20-1.30 (m, 1H), 1.50-2.05 (m, 6H),2.50 (m, 1H), 2.75 (m, 1H), 3.15-3.20 (m, 3H), 3.50 (m, 1H), 3.90 (s,3H), 4.00 (m, 2H), 6.10 (m, 1H), 7.50 (d, 1H), 7.78 (s, 1H), 7.85 (d,1H). LCMS Rt=0.71 minutes; MS m/z 376 [M+H]⁺

Examples 65 and 664-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]methyl}-3,8-diazabicclo[3.2.1]oct-3-yl]-N-(1H-pyrazol-4-yl)pyrimidin-2-amineand4-[(1R,5S)-8-{[(1R)-2,2-difluorocyclopropyl]methyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(1H-pyrazol-4-yl)pyrimidin-2-amine

The title compounds were prepared according to the method described forExamples 63 and 64 using racemic (2,2-difluorocyclopropyl)methyl4-methylbenzenesulfonate (PCT Publication No. WO20130908375) and4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-tosyl-1H-pyrazol-4-yl)pyrimidin-2-amine(Preparation 15). The residue was dissolved in DCM (1 mL) and treatedwith 4N HCl in dioxane (1 mL) and stirred at room temperature for 18hours. MeOH (1 mL) was added and the reaction continued for a further 18hours. The reaction was concentrated in vacuo, eluted through acarbonate cartridge and separated into enantiomers using chiralchromatography as described below:

Column: AD-H 21 mm×250 mm×5μ, Mobile phase A: CO₂; Mobile phase B: MeOH(0.2% ammonium hydroxide) using 75% A and 25% B, Hold for 8 minutes,flow rate 75 mL/min.

First eluting isomer: Rt=5.74 minutes, Example 66; Second elutingisomer: Rt=6.44 minutes, Example 67

Examples 67 and 685-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]methyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamideand5-({4-[(1R,5S)-8-{[(1R)-2,2-difluorocyclopropyl]methyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide

The title compounds were prepared according to the method described forExamples 63 and 64 using5-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-N,3-dimethylpicolinamidehydrochloride (Preparation 1).

The racemate was separated into two enantiomers using chiralchromatography as described below: Column: Chiral Tech OJ-H; 500 mm×21.2mm, 5μ; Mobile phase A 70% CO₂, 30% MeOH (0.2% ammonia), flow rate 80mL/min.

First eluting compound was arbitrarily assigned as Example 67: Rt=6.09minutes, MS m/z 444 [M+H]⁺ Second eluting compound was arbitrarilyassigned as Example 68: Rt=6.21 minutes, MS m/z 444 [M+H]⁺

Examples 69 and 70(1S,2S)-2-{[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methyl}cyclopropanecarbonitrileand(1S,2S)-2-{[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methyl}cyclopropanecarbonitrile

The title compounds were prepared according to the method described forExamples 63 and 64 using (2-cyanocyclopropyl)methyl4-methylbenzenesulfonate (Acta Pharmaceutica Suecica (1972), 9 (5),491-498). The residue was separated into the two enantiomers usingchiral chromatography as described below: Column: OD-H 21 mm×250 mm×5μ,Mobile phase A: CO₂; Mobile phase B: EtOH (0.2% ammonium hydroxide)using 70% A and 30% B, Hold for 7 minutes, flow rate 75 mL/min.

¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.05-1.10 (m, 1H), 1.30 (m, 1H),1.50-1.55 (m, 1H), 1.70 (m, 3H), 2.00 (m, 2H), 3.15-3.40 (m, 4H), 3.50(m, 1H), 3.80 (s, 3H), 4.00 (br m, 2H), 4.80 (m, 1H), 6.10 (m, 1H), 7.55(d, 1H), 7.75 (s, 1H), 7.90 (m, 1H). MS m/z 365 [M+H]⁺

Example 711-({(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methyl)cyclopropanecarbonitrile

The title compound was prepared according to the method described forExample 55 using4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-tosyl-1H-pyrazol-4-yl)pyrimidin-2-amine(Preparation 15) and 1-formylcyclopropane-1-carbonitrile (PCTPublication No. WO2009005675). The residue (5 mg, 0.011 mmol) wasdissolved in MeOH (0.5 mL) and 5N NaOH (aq) (220 μl) was added withstirring for 1 hour. The reaction was concentrated in vacuo, azeotropedwith DCM and purified using preparative HPLC (Purification Method H).Rt=1.06 minutes; MS m/z 351 [M+H]⁺

Example 72N-ethyl-4-({5-fluoro-4-[8-(trifluoroacetyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-2-methylbenzamide

To a solution of4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoropyrimidin-2-yl)amino)-N-ethyl-2-methylbenzamidehydrochloride (Preparation 25, 30 mg, 0.08 mmol) in DCM (5 mL) was addedTFAA (5 drops) and the reaction stirred at room temperature for 18hours. The reaction was purified directly by silica gel columnchromatography eluting with 0-10% MeOH in DCM followed by preparativeHPLC (Purification Method I). Rt=2.22 minutes; MS m/z 481 [M+H]⁺

Example 73 tert tert-butyl3-(2-{[4-(ethylcarbamoyl)-3-methylphenyl]amino}-5-fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

The title compound was prepared according to the method described forPreparation 24 Step 1 using 4-amino-N-ethyl-2-methyl-benzamide (PCTPublication No. WO2006109846). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.13 (t,3H), 1.44-1.49 (m, 9H), 1.74 (d, 2H), 1.89 (br s, 2H), 2.35 (s, 3H),3.18-3.28 (m, 4H), 4.16 (d, 2H), 4.26 (br s, 2H), 7.29 (d, 1H),7.51-7.55 (m, 1H), 7.56 (s, 1H), 8.03-8.09 (m, 2H), 9.30 (s, 1H).

Example 74(1R,5S)-N-ethyl-3-[2-(1,2-thiazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

To a solution ofN-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)isothiazol-4-aminehydrochloride (Preparation 21, 100 mg, 0.27 mmol) in DCM (10 mL) wasadded triethylamine (84 mg, 0.83 mmol) and the solution was cooled to 0°C. Isocyanatoethane (21.7 mg, 0.306 mmol) was added and the reaction wasstirred at room temperature for 18 hours. The reaction was concentratedin vacuo and purified directly by Preparative HPLC (Purification MethodB) to afford the title compound (29 mg, 29%). Preparative HPLC: Column:Phenomenex Gemini C18 250×21.2 mm×24 μm

Mobile phase: from 29% MeCN in water (Ammonia pH=10) to 39% MeCN inwater (Ammonia pH=10); Flow Rate: 30 mL/min. ¹H NMR (400 MHz, DMSO-d₆):δ ppm 1.021 (t, 3H), 1.58-1.59 (m, 2H), 1.77 (m, 2H), 3.01-3.08 (m, 4H),3.96 (m, 2H), 4.35 (s, 2H), 6.23 (d, 1H), 6.67-6.69 (m, 1H), 7.98 (d,1H), 8.59 (s, 1H), 8.75 (s, 1H), 9.68 (s, 1H). MS m/z 382 [M+Na]⁺

Example 75(1R,5S)-3-(2-{[5-chloro-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-N-ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared according to the method described forExample 74 using5-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-3-chloro-N-methylpicolinamidehydrochloride (Preparation 5) and isocyanatoethane. The residue waspurified using preparative HPLC as described below: Preparative HPLC:DIKMA Diamonsil(2) C18 200×20 mm×5 μm

Mobile phase: from 10% MeCN in water (0.225% formic acid) to 30% MeCN inwater (0.225% formic acid). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.02 (t,3H), 1.53-1.63 (m, 2H), 1.74-1.84 (m, 2H), 2.75 (d, 3H), 3.03-3.12 (m,4H), 3.96 (br s, 2H), 4.37 (br s, 2H), 6.36 (d, 1H), 6.72 (t, 1H), 8.05(d, 1H), 8.45 (d, 2H), 8.80 (d, 1H), 9.74 (s, 1H). MS m/z 445 [M+H]⁺

Example 76(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

To a solution of4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19, 30 mg, 0.09 mmol) and sodium isocyanate(14 mg, 0.21 mmol) in DCM (0.3 mL) was added acetic acid (11 μl, 0.186mmol) and the reaction was stirred at room temperature for 18 hours. Thereaction was concentrated in vacuo and purified by reverse phase silicagel column chromatography eluting with 5-50% MeCN in 0.1% aqueousammonia followed by trituration with MeOH and diethylether to afford thetitle compound (26 mg, 85%).

¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.70 (m, 2H), 1.90 (m, 2H), 3.10 (m,2H), 3.90 (s, 3H), 4.00-4.15 (br m, 2H), 4.40 (m, 2H), 6.10 (m, 1H),7.50 (s, 1H), 7.75 (s, 1H), 7.85 (m, 1H).

LCMS Rt=0.50 minutes; MS m/z 329 [M+H]⁺

Example 77N-(1-methyl-1H-pyrazol-4-yl)-4-[(1R,5S)-8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-amine

To a solution of4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19, 100 mg, 0.31 mmol) in DCM (30 mL) at 10°C. was added triethylamine (350 mg, 3.46 mmol) followed by MsCl (280 mg,2.44 mmol). The reaction was stirred at room temperature for 1 hour. Thereaction was washed with water (10 mL) and the organic layer wasconcentrated in vacuo and purified using preparative HPLC (PurificationMethod B) to afford the title compound (70 mg, 62%). ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.55-1.70 (m, 2H), 1.85-2.01 (m, 2H), 3.04 (s, 5H), 3.78(s, 3H), 3.95-4.21 (m, 2H), 4.23-4.36 (m, 2H), 6.02-6.17 (m, 1H), 7.41(s, 1H), 7.65-7.80 (m, 1H), 7.85-7.97 (m, 1H), 8.79-8.95 (m, 1H). MS m/z364 [M+H]⁺

Example 782-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]-1,3-oxazole-5-carbonitrile

A solution of ethyl2-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)oxazole-5-carboxylate(Preparation 136, 200 mg, 0.47 mmol) in 7M NH₃/MeOH (50 mL) was heatedto 90° C. in a sealed vessel for 18 hours. The reaction was concentratedin vacuo and dissolved in DCM (20 mL). Triethylamine (6 mL) followed byTFAA (3 mL) was added and the reaction was stirred at room temperaturefor 18 hours. The solution was washed with saturated aqueous NaHCO₃solution, and concentrated in vacuo. The residue was purified byPreparative HPLC (Purification Method B) to afford the title compound(46 mg, 26%).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.73 (d, 2H), 1.97-2.01 (m, 2H), 3.16(d, 2H), 3.79 (s, 3H), 4.04-4.24 (m, 2H), 4.55 (br s, 2H), 6.14 (d, 1H),7.42 (s, 1H), 7.75 (br s, 1H), 7.92 (d, 1H), 8.04 (s, 1H), 8.98 (br s,1H). MS m/z 378 [M+H]⁺ PM B HATU

Example 793-{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}propanenitrile

To a solution of4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1I2-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 22, 83 mg, 0.308 mmol) and triethylamine (622mg, 6.16 mmol) in EtOH (10 mL) at 0° C. was added acrylonitrile (270 mg,5.09 mmol) dropwise. The reaction was stirred at room temperature for 18hours before concentrating in vacuo. The residue was purified bypreparative HPLC (Purification Method B) to afford the title compound asa white solid (45 mg, 44%).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.43-1.57 (m, 2H), 1.75-1.91 (m, 2H),2.56-2.71 (m, 4H), 2.92-3.05 (m, 2H), 3.37-3.43 (m, 3H), 3.64-4.06 (m,1H), 6.03 (d, 1H), 7.41-7.61 (m, 1H), 7.64-7.79 (m, 1H), 7.87 (d, 1H),8.72-8.87 (m, 1H), 12.33 (br s, 1H). MS m/z 325 [M+H]⁺

Examples 80 and 813-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]butanenitrileand3-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]butanenitrile

The title compound was prepared according to the method described forExample 80 using4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19) and E/Z-but-2-enenitrile at 100° C. in asealed vessel. The residue was purified using silica gel columnchromatography eluting with 5% MeCN in 0.1% aqueous ammonia to 40% MeCNin 0.1% aqueous ammonia followed by chiral separation using a ChiraltechOJ-H 250 mm×10 mm×5 μm column; with mobile phase A: 70% CO₂ and mobilephase B: 30% EtOH with 0.2% ammonia; flow rate 15 mL/min.

First eluting compound was arbitrarily assigned as Example 80: Peak 1Rt=6.69 minutes; LCMS Rt=0.63 minutes MS m/z 353 [M+H]⁺

Second eluting compound was arbitrarily assigned as Example 81: Peak 2Rt=6.95 minutes and is Example 81; LCMS Rt=0.63 minutes; MS m/z 353[M+H]⁺

Example 823-{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}butanenitrile

The title compound was prepared according to the method described forExample 79 using4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1I2-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 22) and E/Z-but-2-enenitrile at 140° C. undermicrowave irradiation for 8 hours. The residue was purified usingreverse phase silica gel column chromatography eluting with from 5-75%MeCN (0.1% ammonia) in water.

¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.50 (d, 3H), 0.90 (m, 2H), 1.00-1.20(m, 2H), 2.10 (m, 1H), 2.30-2.40 (m, 2H), 2.80 (m, 2H), 3.00-3.40 (br m,2H), 4.00 (m, 2H), 5.25 (m, 1H), 6.90 (m, 2H), 7.05 (m, 1H).

LCMS Rt=0.59 minutes; MS m/z 339 [M+H]⁺

Example 83{3-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]-1-(methylsulfonyl)azetidin-3-yl}acetonitrile

The title compound was prepared according to the method described forExample 77 using2-(3-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)azetidin-3-yl)acetonitrilehydrochloride (Example 84) and DIPEA. The residue was purified usingsilica gel column chromatography eluting with 10% MeOH (with 1% ammonia)in DCM.

¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.75-1.90 (m, 4H), 3.05 (s, 3H), 3.20(m, 2H), 3.30 (m, 2H), 3.40 (s, 3H), 3.80 (m, 2H), 3.85 (m, 2H),4.00-4.20 (m, 4H), 6.10 (m, 1H), 7.55 (d, 1H), 7.78 (s, 1H), 7.90 (d,1H).

LCMS Rt=0.52 minutes; MS m/z 458 [M+H]⁺

Example 84{3-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]oxetan-3-yl}acetonitrile

The title compound was prepared according to the method described forPreparation 135 using 2-(3-oxetanylidene)acetonitrile at 85° C. for 5days. The reaction was cooled and purified using Preparative HPLC(Purification Method H). LCMS Rt=1.50 minutes; MS m/z 381 [M+H]⁺

Example 85((1R,5S)-N-(cyanomethyl)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

To a solution of4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19, 26 mg, 0.08 mmol) andN-(cyanomethyl)carbamoylimidazole (Preparation 79, 14 mg, 0.09 mmol) inEtOH (0.8 mL) was added triethylamine (110 μl, 0.082 mmol) in a sealedvessel and the reaction was heated to 60° C. for 2 hours. FurtherN-(cyanomethyl)carbamoylimidazole (2 mg, 0.01 mmol) was added and thereaction continued heating for 2 hours before concentrating in vacuo.The residue was dissolved in DCM (10 mL) and washed with brine, driedover magnesium sulfate and concentrated in vacuo. The residue waspurified using silica gel column chromatography eluting with 0-10% MeOHin DCM to afford the title compound as a white solid (21 mg, 70%). ¹HNMR (400 MHz, MeOH-d₄): δ ppm 1.78 (m, 2H), 2.00 (m, 2H), 3.15 (m, 4H),3.88 (d, 3H), 4.00-4.15 (m, 2H), 4.43 (m, 2H), 6.10 (m, 1H), 7.55 (m,1H), 7.75 (m, 1H), 7.90 (m, 1H). MS m/z 368 [M+H]⁺

Example 86(1R,5S)-N-ethyl-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared according to Example 85 usingN-ethyl-1H-imidazole-1-carboxamide (Preparation 80, 24 mg, 0.17 mmol)and4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19, 50 mg, 0.16 mmol). The residue waspurified using silica gel column chromatography eluting with 0-10% MeOHin DCM to afford the title compound as a white solid (41 mg, 74%). ¹HNMR (400 MHz, DMSO-d₆): δ ppm 1.00 (m, 3H), 1.55 (m, 2H), 1.75 (m, 2H),3.10 (m, 3H), 3.18 (m, 3H) 3.80 (s, 3H), 4.00 (m, 1H), 4.10 (m, 1H),4.40 (m, 2H), 6.10 (m, 1H), 6.67 (t, 1H), 7.45 (s, 1H), 7.73 (br s, 1H),7.91 (d, 1H), 8.82 (s, 1H). LCMS Rt=0.58 minutes; MS m/z 357 [M+H]⁺

Example 87(1R,5S)-N-ethyl-3-(2-{[5-fluoro-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared according to Example 85 usingN-ethyl-1H-imidazole-1-carboxamide (Preparation 80) and5-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-3-fluoro-N-methylpicolinamidehydrochloride (Preparation 14) without triethylamine as base. ¹H NMR(400 MHz, DMSO-d₆): δ ppm 1.04 (t, 3H), 1.60 (q, 2H), 1.81 (d, 2H), 2.78(d, 3H), 2.93-3.14 (m, 4H), 3.18 (d, 2H), 4.39 (br s, 2H), 6.39 (d, 1H),6.71 (t, 1H), 8.07 (d, 1H), 8.27 (d, 1H), 8.42 (d, 1H), 8.71 (s, 1H),9.85 (s, 1H). MS m/z 429 [M+H]⁺

Example 88(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-N-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared according to the method described forExample 85 using N-isopropyl-1H-imidazole-1-carboxamide (Preparation 81)and4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19). Following chromatography the residue wasdissolved in DCM, precipitated by the addition of diethylether andfiltered. LCMS Rt=0.61 minutes; MS m/z 371 [M+H]⁺

Example 89(1R,5S)-3-(2-{[5-methyl-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared according to the method described forExample 85 using5-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-N,3-dimethylpicolinamidehydrochloride (Preparation 1). The residue was purified using silica gelcolumn chromatography eluting with 0-20% MeOH (1% ammonia) in DCM. ¹HNMR (400 MHz, MeOH-d₄): δ ppm 1.80 (m, 2H), 2.00 (m, 2H), 2.60 (s, 3H),2.95 (s, 3H), 3.40 (m, 2H), 3.90-4.00 (m, 2H), 4.15 (br m, 2H), 4.50 (m,2H), 6.30 (m, 1H), 8.00 (m, 2H), 8.75 (m, 1H). LCMS Rt=0.56 minutes; MSm/z 479 [M+H]⁺

Example 90(1R,5S)-N-(cyanomethyl)-3-(2-{[5-methyl-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared according to the method described forExample 85 using5-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-N,3-dimethylpicolinamidehydrochloride (Preparation 1) andN-(cyanomethyl)-1H-imidazole-1-carboxamide (Preparation 78). The residuewas purified using silica gel column chromatography eluting with 0-20%MeOH (1% ammonia) in DCM. ¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.80 (m, 2H),2.00 (m, 2H), 2.65 (s, 3H), 2.95 (s, 3H), 3.20 (m, 2H), 4.20 (m, 4H),4.50 (m, 2H), 6.30 (m, 1H), 8.00 (m, 2H), 8.70 (s, 1H). LCMS Rt=0.50min; MS m/z 436 [M+H]⁺

Example 91(1R,5S)-N-ethyl-3-(2-{[5-methyl-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared according to the method described forExample 85 using5-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-N,3-dimethylpicolinamidehydrochloride (Preparation 1) and N-ethyl-1H-imidazole-1-carboxamide(Preparation 79). Following chromatography the title compound wasfurther purified using Preparative HPLC (Purification Method H). Rt=1.69minutes; MS m/z 425 [M+H]⁺

Example 922-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]pyridine-4-carbonitrile

To a solution of4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19, 51 mg, 0.16 mmol) in iPrOH (1.5 mL) wasadded 4-cyano-2-chloropyridine (45 mg, 0.32 mmol) and triethylamine (100μl, 0.68 mmol). The reaction was heated to 160° C. under microwaveirradiation for 13 hours. The reaction was cooled, concentrated in vacuoand purified using reverse phase silica gel column chromatographyeluting with 5-100% MeCN in 0.1% aqueous ammonia to afford the titlecompound. ¹H NMR (400 MHz, CDCl₃): δ ppm 1.70 (m, 2H), 1.90 (m, 2H),3.10 (m, 2H), 3.70 (s, 3H), 3.80-3.90 (br m, 2H), 4.50 (m, 2H), 5.75 (d,1H), 6.50 (br s, 1H), 6.60-6.70 (m, 2H), 7.35 (s, 1H), 7.50 (s, 1H),7.80 (d, 1H), 8.15 (m, 1H). LCMS Rt=0.74 minutes; MS m/z 388 [M+H]⁺

Examples 93 and 94(1S)-2,2-difluoro-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamideand(1R)-2,2-difluoro-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicclo[3.1.0]hex-1-yl]cyclopropanecarboxamide

To a solution of(1S,5R,6R)-3-(5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-aminehydrochloride (Preparation 90, 148 mg, 0.15 mmol) in DMA (1 mL) and DCM(1 mL) was added racemic 2,2-difluorocyclopropane-1-carboxylic acid (51mg, 0.42 mmol), HATU (188 mg, 0.49 mmol) and DIPEA (279 μl, 0.54 mmol)and the reaction was stirred at room temperature for 18 hours. Thereaction was concentrated in vacuo and partitioned between EtOAc andwater. The organic layer was collected, dried and concentrated in vacuo.The residue was purified using silica gel column chromatography elutingwith from DCM to 91:8:1 DCM:MeOH:ammonia to afford the racemic titlecompound. The racemate was separated using chiral chromatography usingChiralTech AD-H column (250 mm×21.2 mm×5 um); mobile phase A: 80% CO₂;mobile phase B: 20% MeOH with 0.2% ammonia. The residue for eachenantiomer may be purified further by recrystallization from MeOH.

Peak 2 Rt=5.89 minutes Example 93:

¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.05-1.10 (m, 3H), 1.36-1.43 (m, 1H),1.73-1.82 (m, 1H), 1.86-1.90 (m, 1H), 1.98-2.06 (m, 1H), 2.45-2.53 (m,1H), 3.75-3.83 (m, 2H), 3.86 (s, 3H), 4.10 (m, 2H), 7.50 (s, 1H), 7.76(d, 1H), 7.80 (s, 1H).

LCMS Rt=0.57 minutes; MS m/z 408 [M+H]⁺

Peak 1 Rt=3.90 minutes Example 94:

¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.05-1.10 (m, 3H), 1.40 (m, 1H), 1.75(m, 1H), 1.80 (m, 1H), 2.00 (m, 1H), 2.50 (m, 1H), 3.60-3.80 (m, 5H),4.10 (m, 2H), 7.50 (s, 1H), 7.80 (m, 2H).

LCMS Rt=0.57 minutes; MS m/z 408 [M+H]⁺; [α]_(D) ²⁰=16.8 (c 1.095, MeOH)

Example 95(1R,2R)-2-cyano-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide

The title compound was prepared according to the method described forExample 93 using (1R,2R)-2-cyanocyclopropane-1-carboxylate (Preparation72).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.90 (m, 3H), 1.25-1.35 (m, 4H), 1.45(m, 1H), 1.80 (m, 1H), 2.00 (m, 1H), 2.20 (m, 1H), 3.60-3.80 (m, 3H),3.90 (m, 2H), 7.40 (s, 1H), 7.70 (s, 1H), 7.90 (d, 1H), 9.00 (br s, 1H),9.10 (s, 1H). MS m/z 397 [M+H]⁺; [α]_(D) ²⁰=−113.3 (c 0.965, EtOH)

The following Examples were prepared according to the method describedfor Example 93 using the appropriate acid and amine as described.Purification details are as described or referred to below: PurificationMethod A: Purified using preparative HPLC: Column: Diol, 250 mm×21.2mm×5 μm; mobile phase A: heptanes; mobile phase B: ethanol; from 50% Bto 100% B at 10 minutes then return to 50% B at 12 minutes; Flow rate 27mL/min.

Analytical LCMS: Phenomenex Luna C18; 150 mm×3 mm×5 μm, mobile phase A:0.1% formic acid in water, mobile phase B: 0.1% formic acid inacetonitrile from 5% B to 100% B at 10 minutes then return to 5% B at12.5 minutes. Flow rate 0.75 mL/min.

Purification Method B: Silica gel column chromatography eluting with97:2:1 DCM:MeOH:NH₄OH.

Purification Method C: Preparative HPLC using [Phenomenex Gemini C18250×21.2 mm×8 μm or 150 mm×25 mm×5 μm; from 16-55% MeCN in water (0.1%ammonia) to 36-60% MeCN in water (0.1% ammonia)]

Ex. No. Structure/name Starting Materials Data 96 (1S)-2,2-difluoro-N-(1R,5S,6S)-3-(5-fluoro-2- LCMS Rt = 0.50 [(1R,5S,6S)-3-{5-fluoro-2-((1-methyl-1H-pyrazol-4- minutes MS m/z 408 [(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)- [M + H]⁺ yl)amino]pyrimidin-4-yl}-6-6-methyl-3-azabicyclo- [α]_(D) ²⁰ = 0 (c 1.095, methyl-3-[3.1.0]hexan-1-amine EtOH) azabicyclo[3.1.0]hex-1- hydrochloride ¹H NMR(400 MHz, yl]cyclopropanecarboxamide (Preparation 91) and DMSO-d₆): δppm 0.90 (S)-2,2-difluoro- (m, 5H), 1.30 (m, 1H), cyclopropane-1-1.70-2.00 (m, 3H), 2.40 carboxylic acid (m, 1H), 3.60-3.80 (m,(Preparation 68). 5H), 7.40 (s, 1H), 7.70 (s, 1H), 7.90 (m, 1H),8.90-9.00 (m, 2H). PM B. 97 (1R)-2,2-difluoro-N-(1R,5S,6S)-3-(5-fluoro-2- LCMS Rt = 0.50 [(1R,5S,6S)-3-{5-fluoro-2-((1-methyl-1H-pyrazol-4- minutes MS m/z 408 [(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)- [M + H]⁺ yl)amino]pyrimidin-4-yl}-6-6-methyl-3-azabicyclo- [α]_(D) ²⁰ = −7.1 (c 1.095, methyl-3-[3.1.0]hexan-1-amine EtOH) azabicyclo[3.1.0]hex-1- hydrochloride ¹H NMR(400 MHz, yl]cyclopropanecarboxamide (Preparation 91) and DMSO-d₆): δppm 0.90 (R)-2,2-difluoro- (m, 5H), 1.30 (m, 1H), cyclopropane-1-1.70-2.00 (m, 3H), 2.40 carboxylic acid (m, 1H), 3.60-4.00 (m,(Preparation 69). 5H), 7.40 (s, 1H), 7.70 (s, 1H), 7.90 (m, 1H),8.90-9.00 (m, 2H). PM B. 98 (1S,2S)-2-cyano-N- 2-((5-((4-((1S,5R,6R)-1-Rt = 5.64 minutes [(1S,5R,6R)-3-(2-{[6-(2- amino-6-methyl-3- MS m/z 450[M + H]⁺ hydroxyethoxy)pyridin-3- azabicyclo[3.1.0]hexan- PM A.yl]amino}-5-methylpyrimidin- 3-yl)-5-methylpyrimidin- 4-yl)-6-methyl-3-2-yl)amino)pyridin-2- azabicyclo[3.1.0]hex-1- yl)oxy)ethan-1-olyl]cyclopropanecarboxamide (Preparation 92) and (1S,2S)-2-cyano-cyclopropane-1- carboxylic acid (Preparation 73). 99(1S)-2,2-difluoro-N- (1S,5R,6R)-3-(5-fluoro-2- ¹H NMR (400 MHz,[(1S,5R,6R)-3-(5-fluoro-2- ((1-(oxetan-3-yl)-1H- MeOH-d₄): δ ppm 1.03{[1-(oxetan-3-yl)-1H-pyrazol- pyrazol-4- (d, 3H), 1.31-1.40 (m,4-yl]amino}pyrimidin-4-yl)-6- yl)amino)pyrimidin-4-yl)- 1H), 1.71-1.89(m, 2H), methyl-3- 6-methyl-3- 1.99 (dt, 1H), 2.41-2.53azabicyclo[3.1.0]hex-1- azabicyclo[3.1.0]hexan- (m, 1H), 3.73-3.85 (m,yl]cyclopropanecarboxamide 1-amine (Preparation 2H), 4.08 (dd, 2H),4.95- 93) and (S)-2,2- 5.09 (m, 4H), 5.48 (m, difluorocyclopropane-1 -1H), 7.63 (s, 1H), 7.75 carboxylic acid (d, 1H), 8.04 (s, 1H).(Preparation 68). MS m/z 450 [M + H]⁺ PM C.

Examples 100 and 101 5-[(4-{(1S5R,6R)-1-[(cyclopropylcarbonyl)amino]-6-methyl-3-azabicyclo[3.1.0.]hex-3-yl}-5-fluoropyrimidin-2-yl)aminol]-N,3-dimethylpyridine-2-carboxamideand5-(4-{10R,5S6S)-1-[(cyclopropylcarbonyl)aminol-6-methyl-3-azabicyclo[3.1.0]hex-3-yl}-5-fluoropyrimidin-2-yl)amino]-N,3-dimethylpyridine-2-carboxamide

The title compounds were prepared according to the method described forExample 5 using trans-racemicN-(3-(2-chloro-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)cyclopropane-carboxamide(Preparation 95) and 5-amino-N,3-dimethylpicolinamide (Preparation 38).The residue was purified and separated in enantiomers by chiralchromatography: Chiral column: Lux Cellulose-4, 250 mm×21.2 mm×5 μm,mobile phase A: supercritical CO₂, mobile phase B: Methanol, A:B 65:35;flow rate 80 mL/min. First eluting isomer: Example 100; Second elutingisomer: Example 101.

MS m/z 440 [M+H]⁺

Example 102N-[(1S,5R,6R)-3-(5-fluoro-2-{[6-(2-hydroxyethyl)pyridin-3-yl]amino}pyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide

The title compound was prepared according to the method described forExample 5 usingN-((1S,5R,6R)-3-(2-chloro-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamide(Preparation 95) and 2-(5-aminopyridin-2-yl)ethan-1-ol (Preparation116). The residue was purified by silica gel column chromatographyeluting with 10% MeOH in DCM followed by preparative HPLC (PurificationMethod B). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.64-0.66 (m, 4H), 0.90 (d,3H), 1.24-1.28 (m, 1H), 1.49 (m, 1H), 1.76-1.77 (m, 1H), 2.76-2.80 (m,2H), 3.39 (s, 1H), 3.64-3.70 (m, 4H), 3.87-3.88 (m, 1H), 4.59-4.61 (m,1H), 7.13 (d, 1H), 7.94 (d, 1H), 7.97 (d, 1H), 8.71 (s, 1H), 8.74 (s,1H), 9.20 (s, 1H). MS m/z 413 [M−H]⁻

Examples 103 and 104 NN-{(1S,5R,6R)-3-[5-fluoro-2-({6-[(2R)-1-hydroxpropan-2-yl]pridin-3-yl}amino)pyrimidin-4-yl]-6-methyl-3-azabicyclo[3.1.0]hex-1-yl}cyclopropanecarboxamideandN-{(1S,5R,6R)-3-[5-fluoro-2-({6-[(2S)-1-hydroxypropan-2-yl]pyridin-3-yl}amino)pyrimidin-4-yl]-6-methyl-3-azabicyclo[3.1.0]hex-1-yl}cyclopropanecarboxamide

The title compounds were prepared according to the method described forExample 5 usingN-((1S,5R,6R)-3-(2-chloro-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamide(Preparation 95) and racemic-2-(5-aminopyridin-2-yl)propan-1-ol(Preparation 40). The residue was purified using silica gel columnchromatography eluting with 10% MeOH in DCM followed by preparative HPLC(Preparation Method B). The racemate was separated into its enantiomersusing chiral chromatography:

Chiral column: Chiralpak IC, 250 mm×30 mm×5 μm, mobile phase A:supercritical CO₂, mobile phase B: IPA (0.1% ammonia), A:B 60:40; flowrate 70 mL/min.

First eluting isomer was arbitrarily assigned as Example 103;

¹H NMR (400 MHz, MeOH-d₄): δ ppm 0.76-0.86 (m, 4H), 1.00-1.02 (m, 3H),1.28-1.38 (m, 4H), 1.54 (m, 1H), 1.76-1.83 (m, 1H), 3.00-3.05 (m, 1H),3.66-3.80 (m, 4H), 4.03-4.05 (m, 2H), 7.23-7.27 (d, 1H), 7.80-7.81 (d,1H), 8.04-8.05 (d, 1H), 8.84 (s, 1H). MS m/z 449 [M+Na]⁺, 99.2% ee.

Second eluting isomer was arbitrarily assigned as Example 104;

¹H NMR (400 MHz, MeOH-d₄): δ ppm ¹H NMR (400 MHz, MeOH-d₄): δ ppm0.76-0.86 (m, 4H), 1.00-1.02 (m, 3H), 1.28-1.38 (m, 4H), 1.54 (m, 1H),1.76-1.83 (m, 1H), 3.00-3.05 (m, 1H), 3.66-3.80 (m, 4H), 4.03-4.05 (m,2H), 7.23-7.27 (d, 1H), 7.80-7.81 (d, 1H), 8.04-8.05 (d, 1H), 8.84 (s,1H).

MS m/z 449 [M+Na]⁺, 94% ee.

Example 105N-[(1S,5R,6R)-3-(2-{[5-chloro-6-(hydroxymethyl)pyridin-3-yl]amino}-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide

The title compound was prepared according to the method described forExample 5 usingN-((1S,5R,6R)-3-(2-chloro-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamide(Preparation 95) and (5-amino-3-chloropyridin-2-yl)methanol (Preparation122). The residue was purified using silica gel column chromatographyeluting with 30% petroleum ether in EtOAc followed by preparative HPLC(Purification Method B).

¹H NMR (400 MHz, MeOH-d₄): δ ppm 0.76-0.78 (m, 2H), 0.86 (m, 2H),1.01-1.03 (m, 3H), 1.35-1.37 (m, 1H), 1.53 (m, 1H), 1.82 (m, 1H),3.75-3.78 (m, 2H), 4.04 (m, 2H), 4.72 (s, 2H), 7.85 (m, 1H), 8.45 (s,1H), 8.65 (s, 1H). MS m/z 433 [M+H]⁺

Example 106N-{(1S,5R,6R)-3-[2-({5-chloro-6-[(1R)-1-hydroxyethyl]pyridin-3-yl}amino)-5-fluoropyrimidin-4-yl]-6-methyl-3-azabicyclo[3.1.0]hex-1-yl}cyclopropanecarboxamide

To a solution of tert-butyl((1S,5R,6R)-3-(2-((5-chloro-6-((S)-1-hydroxyethyl)pyridin-3-yl)amino)-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate(Preparation 138 350 mg, 0.718 mmol) in MeOH (10 mL) was added 4M HCl indioxane (10 mL, 4M) dropwise. The solution was stirred at roomtemperature for 1 hour before concentrating in vacuo. The residue (54mg, 0.143 mmol) was dissolved in DMF (10 mL) and treated withtriethylamine (86 mg, 0.85 mmol) cyclopropanecarboxylic acid (24 mg,0.28 mmol) and HATU (86 mg, 0.23 mmol). The reaction was stirred at roomtemperature for 18 hours. The reaction was concentrated in vacuo andpurified directly using preparative HPLC (Purification Method B) toafford the title compound (38 mg, 58%).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.62-0.73 (m, 3H), 0.93 (s, 2H),1.16-1.21 (m, 1H), 1.24-1.31 (m, 1H), 1.37 (d, 2H), 1.46-1.56 (m, 1H),1.72-1.85 (m, 1H), 3.06-3.15 (m, 1H), 3.58-3.76 (m, 1H), 3.86-3.97 (m,1H), 4.97-5.08 (m, 1H), 7.98-8.05 (m, 1H), 8.29-8.40 (m, 1H), 8.69-8.79(m, 2H), 9.50-9.60 (m, 1H).

MS m/z 447 [M+H]⁺

Examples 107 and 108N-[(1S,5R)-3-(5-chloro-2-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}pyrimidin-4-yl)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamideandN-[(1R,5S)-3-(5-chloro-2-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}pyrimidin-4-yl)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide

The racemic title compound was prepared according to the methoddescribed for Example 49 usingracemic-N-(3-(2,5-dichloropyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamide(Preparation 98) and 4-amino-1H-pyrazole-1-ethanol.

The racemate was separated into its enantiomers using preparative chiralchromatography as described below:

Chiral column: Chiralpak Ad 250 mm×30 mm I.D. 20 μm; Mobile phase:supercritical C₂:EtOH (0.2% ammonia) 45:55; Flow rate: 80 mL/min

First Eluting Isomer: Example 107

¹H NMR (400 MHz, MeOH-d₄): δ ppm 0.76-0.79 (m, 3H), 0.86-0.87 (m, 2H),1.10 (m, 1H), 1.28 (m, 1H), 1.54 (m, 1H), 1.76 (m, 1H), 3.73 (m, 1H),3.87 (m, 2H), 3.91-3.94 (m, 1H), 4.16 (m, 3H), 4.47-4.49 (m, 1H), 7.52(s, 1H), 7.81 (s, 1H), 7.87 (s, 1H). MS m/z 404 [M+H]⁺

Second Eluting Isomer: Example 108

¹H NMR (400 MHz, MeOH-d₄): δ ppm 0.76-0.79 (m, 3H), 0.86-0.87 (m, 2H),1.10 (m, 1H), 1.28 (m, 1H), 1.54 (m, 1H), 1.76 (m, 1H), 3.73 (m, 1H),3.87 (m, 2H), 3.91-3.94 (m, 1H), 4.16 (m, 3H), 4.47-4.49 (m, 1H), 7.52(s, 1H), 7.81 (s, 1H), 7.87 (s, 1H). MS m/z 404 [M+H]⁺

Example 109(1S)-2,2-difluoro-N-[(1S,5S)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide

The title compound was prepared according to the method described forExample 49 using(S)-N-((1S,5S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-2,2-difluorocyclopropane-1-carboxamide(Preparation 88) and 1-methyl-1H-pyrazol-4-ylamine at 85° C. The residuewas purified using silica gel column chromatography eluting with 0-5%MeOH in DCM.

¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.78-1.88 (m, 1H), 2.00-2.10 (m, 1H),2.55-2.65 (m, 1H), 3.70 (m, 1H), 3.70 (m, 1H), 3.90 (s, 3H), 3.95-4.00(m, 1H), 4.10-4.20 (m, 1H), 7.50 (s, 1H), 7.80 (s, 2H).

MS m/z 424 [M+H]⁺

Example 110(1R,2R)-2-cyano-N-[(1S,5S)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide

The title compound was prepared according to the method described byExample 109 usingracemic-(1R,2R)-N-(3-(2-chloro-5-fluoropyrimidin-4-yl)-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-2-cyanocyclopropane-1-carboxamide(Preparation 89). The racemate was separated into its enantiomers usingchiral chromatography as described below:

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.05 (d, 1H), 1.13 (m, 1H), 1.50 (m,2H), 2.02 (m, 1H), 2.33 (m, 1H), 3.60-3.79 (m, 4H), 3.87 (s, 3H), 3.98(m, 1H), 4.09 (m, 1H), 4.16 (m, 1H), 7.54 (s, 1H), 7.77-7.78 (m, 2H).

Column: Cellulose-3 21 mm×250 mm×5 μm; Mobile phase A: CO₂, Mobile phaseB: MeOH; 90:10 A:B; hold for 10 minutes; 65 mL/min. Peak 2; Rt=7.08minutes, MS m/z 413 [M+H]⁺

Example 1114-({4-[6-(2,2-difluoropropanoyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]-5-fluoropyrimidin-2-yl}amino)-N-ethyl-2-methylbenzamide

To a solution of4-((4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-fluoropyrimidin-2-yl)amino)-N-ethyl-2-methylbenzamide(Preparation 126, 25 mg, 0.067 mmol) in DCM (5 mL) was added2,2-difluoropropanoic acid (7 mg, 0.067 mmol), HATU (25 mg, 0.066 mmol)and triethylamine (0.03 mL, 0.2 mmol). The reaction was stirred at roomtemperature for 1 hour. The reaction was diluted with water, the organicphase collected through a phase separation cartridge and concentrated invacuo. The residue was purified using preparative HPLC (Method 1, 5% Bto 50% B in 8.5 min, to 100% B in 9 min, hold at 100% B to 10 min) toafford the title compound.

Preparative HPLC Conditions

Method 1: Waters Sunfire C18 19×500 mm, 5μ, Mobile Phase A: 0.05% TFA inwater; Mobile Phase B: 0.05% TFA in Acetonitrile. Flow rate 25 mL/min.

Method 2: Waters Sunfire C18 19×500 mm, 5μ, Mobile Phase A: 0.05% Formicacid in water; Mobile Phase B: 0.05% Formic acid in Acetonitrile. Flowrate 25 mL/min.

LCMS QC Conditions:

Column: Waters Atlantis dC18 4.6×50 mm, 5μ

Modifier: TFA 0.05%

Gradient: 95% water:5% MeCN linear to 5% water:95% MeCN over 4 minutes,hold for 1 minute to 5 minutes. Flow rate: 2 mL/min

MS mode: ESI+; scan range 160-650 Da

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.15 (t, 3H), 1.77-1.88 (m, 4H), 2.37(s, 3H), 2.86 (q, 1H), 3.23-3.30 (m, 2H), 4.02-4.09 (m, 2H), 4.09-4.19(m, 2H), 4.65 (br s, 1H), 4.92 (br s, 1H), 7.31 (d, 1H), 7.60 (br s,2H), 8.05-8.12 (m, 2H), 9.36 (s, 1H). LCMS Rt=1.96 minutes; MS m/z 463[M+H]⁺

Example 112N-ethyl-4-({5-fluoro-4-[6-(2-fluoro-2-methylpropanoyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2-yl}amino)-2-methylbenzamide

The title compound was prepared, purified and analysed as described forExample 111 using 2-fluoro-2-methylpropanoic acid and4-((4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-fluoropyrimidin-2-yl)amino)-N-ethyl-2-methylbenzamide(Preparation 126).

Prep. HPLC Method 1, 10% B to 50% B in 8.5 min, to 100% B in 9 min, holdat 100% B to 10 min.

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.13 (t, 3H), 1.38-1.49 (m, 3H),1.52-1.61 (m, 3H), 1.74 (d, 1H), 2.35 (s, 3H), 2.77 (q, 1H), 3.20-3.28(m, 2H), 3.94 (d, 1H), 4.02 (d, 1H), 4.06-4.13 (m, 1H), 4.17 (d, 1H),4.52 (br s, 1H), 4.82 (br s, 1H), 7.28 (d, 1H), 7.54-7.63 (m, 2H), 8.05(d, 2H), 9.31 (s, 1H).

LCMS Rt=1.95 minutes; MS m/z 459 [M+H]⁺

Example 1134-({4-[6-(cyclopropylcarbonyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2-yl}amino)-N-ethyl-2-methylbenzamide

The title compound was prepared, purified and analysed as described forExample 111 using cyclopropanecarboxylic acid and tert-butyl3-(2-chloropyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptanes-6-carboxylatehydrochloride (Preparation 128).

Preparative HPLC Method 2, 5% B to 100% B in 8.5 min, hold at 100% B to10 min.

LCMS Rt=1.57 minutes; MS m/z 421 [M+H]⁺

Example 1144-({4-[6-(2,2-difluoropropanoyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2-yl}amino)-N-ethylbenzamide

The title compound was prepared, purified and analysed as described forExample 115 using 2,2-difluoropropanoic acid and4-((4-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrimidin-2-yl)amino-N-ethylbenzamidehydrochloride (Preparation 127).

Prep. HPLC Method 1, 10% B to 60% B in 8.5 min, to 100% B in 9 min, holdat 100% B to 10 min.

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.17 (t, 3H), 1.76-1.88 (m, 4H),2.87-2.95 (m, 1H), 3.28-3.37 (m, 2H), 3.84-4.14 (m, 4H), 4.70 (br s,1H), 4.97 (br s, 1H), 6.51 (d, 1H), 7.75-7.83 (m, 2H), 7.91 (br s, 2H),8.14 (d, 1H), 8.42 (br s, 1H), 10.48 (br s, 1H). LCMS Rt=1.93 minutes;MS m/z 431 [M+H]⁺

Example 115N-ethyl-2-methyl-4-({4-[6-(trifluoroacetyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2-yl}amino)benzamide

To a solution of4-((4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrimidin-2-yl)amino)-N-ethyl-2-methylbenzamidehydrochloride (Preparation 128, 30 mg, 0.077 mmol) in DCM (5 mL) wasadded triethylamine (0.1 mL, 0.7 mmol) followed by TFAA (2 drops). Thereaction was stirred at room temperature for 2 hours, concentrated invacuo and purified and analysed using preparative HPLC (Method 2, 5% Bto 100% B in 8.5 min, hold at 100% B to 10 min) as described for Example111 to afford the title compound. LCMS Rt=1.76 minutes; MS m/z 449[M+H]⁺

Example 116N-ethyl-4-({5-fluoro-4-[6-(trifluoroacetyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2-yl}amino)-2-methylbenzamide

A solution of1-(3-(2-chloro-5-fluoropyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-2,2,2-trifluoroethan-1-one(Preparation 129, 100 mg, 0.31 mmol) and4-amino-N-ethyl-2-methylbenzamide (PCT Publication No. WO2006109846) inisopropanol (3 mL) was treated with 1 drop of cHCl and heated to 140° C.for 40 minutes under microwave irradiation. The reaction was cooled,concentrated in vacuo and taken on directly to the next step.

Example 1175-({4-[(1R,5S)-8-{[(1S)-2,2-Difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3-fluoropyridine-2-carboxamide

To a solution of Preparation 144 (280 mg, 0.815 mmol) and Preparation 68(129 mg, 1.06 mmol) in DMF (30 mL) was added TEA (330 mg, 3.26 mmol) andHATU (372 mg, 0.979 mmol) at 0° C. The mixture was stirred at roomtemperature (10° C.) for 18 h. The solution was concentrated andpurified by Preparative HPLC

Preparative HPLC Conditions

Phenomenex Synergi C18 150×30 mm, 4p, Mobile Phase A: acetonitrile;Mobile Phase B: water (adjusted to pH 10 with ammonia). Flow Rate: 35mL/min. LCMS: (M+1=447.9, M+23=469.9) The racemate was separated usingchiral chromatography using Chiralpal AS-H column (150 mm×4.6 mm×5 um);mobile phase A: 5% CO₂ to 40%; mobile phase B: MeOH with 0.05% DEA toprovide the title compound (143 mg, 39%) at Rt=8.12 minutes. LCMSRt=0.73 minutes, MS m/z 448.1 [M+H]

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.58-2.10 (m, 6H), 2.93-3.28 (m, 3H),4.04-4.33 (m, 2H), 4.57-4.78 (m, 2H), 6.41 (dd, 1H), 7.37 (br. s., 1H),7.80 (br. s., 1H), 8.10 (dd, 1H), 8.27 (m, 1H), 8.67 (d, 1H), 9.88 (s,1H).

Preparation 15-((4-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-N,3-dimethylpicolinamidehydrochloride

Step 1

To tert-butyl(1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(Preparation 34, 500 mg, 1.54 mmol) and 5-amino-N,3-dimethylpicolinamide(Preparation 38, 458 mg, 2.78 mmol) in DMA (20 mL) was added cesiumcarbonate (1 g, 3.08 mmol), xantphos (178 mg, 0.31 mmol) and palladiumacetate (69 mg, 0.31 mmol). The reaction was purged with nitrogen for 1minute before heating to 130° C. under microwave irradiation for 1 hour.The reaction was cooled, filtered and concentrated in vacuo. The residuewas purified using silica gel column chromatography eluting with 50-80%EtOAc in petroleum ether.

Step 2

The resulting solid was dissolved in DCM (20 mL) and treated with 4M HClin dioxane (20 mL) and the reaction was stirred at room temperature for2 hours. The reaction was concentrated in vacuo to afford the titlecompound as the hydrochloride salt. ¹H NMR (400 MHz, DMSO-d₆): bppm1.67-1.83 (m, 2H), 1.90-2.06 (m, 2H), 2.58 (s, 3H), 2.78 (br s, 3H),3.59-3.72 (m, 2H), 4.16-4.27 (m, 4H), 6.66-6.77 (n, 1H), 7.88 (br s,1H), 8.17 (d, 1H), 8.46-8.60 (n, 1H), 8.66 (br s, 1H), 9.61-9.75 (n,1H), 10.03-10.16 (n, 1H), 11.09 (br s, 1H).

MS m/z 354 [M+H]³⁰

The following preparations were prepared according to the methoddescribed by Preparation 1 usingtert-butyl(1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(Preparation 34) and the appropriate amine as described below. Thecompounds were isolated as the hydrochloride salts unless otherwisespecified.

Deprotection Method B: The Boc-protected intermediate was dissolved inDCM, treated with TFA and stirred at room temperature for 18 hours. Thereaction was basified to pH=10 by the addition of triethylamine. Thesolution was concentrated in vacuo and purified by silica gel columnchromatography eluting with 10% MeOH in EtOAc or 96:3:1 DCM:MeOH:NH₃.

Deprotection Method C: The Boc-protected intermediate was dissolved inDCM, treated with TFA and stirred at room temperature for 1.5 hours. Thereaction was concentrated in vacuo, dissolved in MeOH and eluted througha carbonate cartridge to afford the free parent.

Prepar- ation number Structure Name SM/Data  2

Racemic 2-(5-((4- ((1R,5S)-3,8-diazabi- cyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)- pyridin-2-yl)propan-1-ol hydrochloride Racemic2-(5-aminopyridin- 2-yl)propan-1-ol (Preparation 40). Taken on directlyto the next step.  3

5-((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)- N-ethyl-3-methylpicol- inamide hydrochloride5-amino-N-ethyl-3- methylpicolinamide (Preparation 42). Taken ondirectly to the next step.  4

4-((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)- N-ethylbenzamide hydrochloride4-amino-N-ethyl benzamide. Taken on directly to the next step.  5

5-((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)- 3-chloro-N- methylpicolinamide hydrochloride5-amino-3-chloro-N- methylpicolinamide (Preparation 39).Taken ondirectly to the next step.  6

2-(5-((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)- 3-chloropyridin-2-yl)ethan- 1-olhydrochloride 2-(5-amino-3-chloropyridin- 2-yl)ethan-1-ol (Preparation45). Taken on directly to the next step.  7

2-(5-((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)- 3-fluoropyridin-2-yl)ethan- 1-olhydrochloride 2-(5-amino-3-fluoropyridin- 2-yl)ethan-1-ol (Preparation46). Taken on directly to the next step.  8

(S)-1-(5-((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)- 3-fluoropyridin-2- yl)pyrrolidin-3-olhydrochloride (S)-1-(5-amino-3- fluoropyridin-2-yl)pyrrolidin- 3-ol(Preparation 47). Taken on directly to the next step.  9

(R)-1-(5-((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)- 3-fluoropyridin-2- yl)pyrrolidin-3-olhydrochloride (R)-1-(5-amino-3- fluoropyridin-2-yl)pyrrolidin- 3-ol(Preparation 48). Taken on directly to the next step. 10

1-(5-((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)- 3-fluoropyridin-2- yl)azetidin-3-olhydrochloride 1-(5-amino-3-fluoropyridin- 2-yl)azetidin-3-ol(Preparation 49). Taken on directly to the next step. 11

2-((5-((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)- 3-chloropyridin-2- yl)oxy)ethan-1-olhydrochloride 2-((5-amino-3-chloropyridin- 2-yl)oxy)ethan-1-ol(Preparation 50). Taken on directly to the next step. 12

(5-((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)- 3-fluoropyridin-2- yl)methanol hydrochloride5-amino-3-fluoro-2-pyridine methanol (PCT Publication No. WO2013013815)Taken on directly to the next step. 13

2-(5-((4-((1R,5S)-3,8 diazabicyclo[3.2.1]octan- 3-yl)pyrimidin-2-yl)amino)pyridin-2-yl)-2- methylpropanenitrile2-)5-aminopyridin-2-yl)-2- methylpropanenitrile and using deprotectionmethod B. 14

5-((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)- 3-fluoro-N- methylpicolinamide hydrochloride5-amino-3-fluoro-N- methylpicolinamide (Preparation 51). 15

4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan- 3-yl)-N-(1-tosyl-1H-pyrazol-4-yl)pyrimidin-2- amine 1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-amine (PCT Publication No. WO2011106114). Deprotectionmethod C. LCMS Rt = 0.73 minutes MS m/z 426 [M + H]⁺ 16

4-((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)- N,6-dimethylpicolinamide 4-amino-N,6-dimethylpicolinamide (Preparation 44). Deprotection method B. LCMS Rt =0.39 minutes MS m/z 354 [M + H]⁺ 17

4-((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)- 6-(hydroxymethyl)-N- methylpicolinamidehydrochloride 4-amino-6-(hydroxymethyl)- N-methylpicolinamidehydrochloride (Preparation 125). Taken on directly to the next step.

Preparation 185-((4-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-3-methylpicolinamidehydrochloride

The title compound was prepared according to the method described forPreparation 1 Step 1. Following the Buchwald step the intermediate washeated with ammonia in methanol to 90° C. in a sealed vessel. Thereaction was cooled and concentrated in vacuo before deprotection withHCl as described.

Preparation 194-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride

A solution of tert-butyl(1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(Preparation 34, 2.25 g, 6.93 mmol) and 1-methyl-1H-pyrazol-4-ylaminehydrochloride (1.02 g, 7.62 mmol) in iPrOH (30 mL) was heated to 140° C.under microwave irradiation for 1 hour. The reaction was concentrated invacuo to afford the title compound as the hydrochloride salt (2.2 g,99%). ¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.97-2.02 (m, 2H), 2.19-2.20 (m,2H), 3.48-3.51 (m, 1H), 3.72-3.78 (m, 1H), 3.98 (s, 3H), 4.20-4.31 (m,3H), 6.67 (d, 1H), 7.81 (s, 1H), 7.86 (m, 2H). MS m/z 286 [M+H]⁺

Preparation 202-(4-((4-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)ethan-1-olhydrochloride

To a solution of tert-butyl(1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(Preparation 34, 200 mg, 0.617 mmol) and 4-amino-1H-pyrazole-1-ethanol(134 mg, 0.74 mmol) in iPrOH (10 mL) was added 3 drops of concentratedHCl at room temperature. The reaction was heated to 140° C. undermicrowave irradiation for 40 minutes. The reaction was concentrated invacuo to afford the title compound and taken on directly to the nextstep as the hydrochloride salt.

The following preparations were prepared according to the methoddescribed by Preparation 20 using tert-butyl(1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(Preparation 34) and the appropriate amine as described below. Thecompounds were isolated as the hydrochloride salts.

Prepar- ation number Structure Name SM/Data 21

N-(4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)isothiazol-4- amine hydrochloride MS m/z 289 [M + H]⁺4-isothiazolamine 22

4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3- yl)-N-(1I2-pyrazol-4-yl)pyrimidin-2-amine hydrochloride tert-butyl 4-amino-1H-pyrazole-1-carboxylate (PCT Publication No. WO2012022681). 23

4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3- yl)-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine hydrochloride MS m/z 300 [M + H]⁺1-ethyl-1H-pyrazol-4-amine

Preparation 244-((4-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoropyrimidin-2-yl)amino)-N-ethylbenzamidehydrochloride

Step 1

To a solution of tert-butyl(1R,5S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(Preparation 35, 0.5 g, 1.5 mmol) in dioxane (5 mL) was added4-amino-N-ethyl benzamide (0.26 g, 1.6 mmol), RuPHOS palladium (II)phenethylamine chloride (0.1 g, 0.1 mmol) and sodium tert-butoxide (0.15g, 1.5 mmol). The reaction was heated to 120° C. under microwaveirradiation for 25 minutes. The reaction was cooled and eluted through asolid phase extraction cartridge. The filtrate was purified using silicagel column chromatography eluting with 0-20% MeOH in DCM to affordboc-protected intermediate (0.65 g, 95%).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.07 (t, 3H), 1.37-1.41 (m, 9H), 1.67(d, 2H), 1.78-1.86 (m, 2H), 3.13-3.18 (m, 2H), 3.18-3.26 (m, 2H),4.07-4.13 (m, 2H), 4.20 (br s, 2H), 7.65-7.69 (m, 2H), 7.69-7.74 (m,2H), 8.02 (d, 1H), 8.19 (t, 1H), 9.43 (s, 1H).

Step 2

The intermediate was dissolved in DCM (5 mL) and MeOH (2 mL) and treatedwith 4M HCl in dioxane. The reaction was stirred at room temperature for18 hours before concentrating in vacuo to afford the title compound asthe hydrochloride salt.

Preparation 254-((4-((1R,5S)-3,8-Diazabicclo[3.2.1]octan-3-yl)-5-fluoropyrimidin-2-yl)amino)-N-ethyl-2-methylbenzamidehydrochloride

tert-Butyl(1R,5S)-3-(2-((4-(ethylcarbamoyl)-3-methylphenyl)amino)-5-fluoropyrimidin-4-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylate(Example 74) was dissolved in DCM (5 mL) and MeOH (2 mL) and treatedwith 4M HCl in dioxane. The reaction was stirred at room temperature for18 hours before concentrating in vacuo to afford the title compound asthe hydrochloride salt.

Preparation 265-((4-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-3-methylpicolinamidehydrochloride

A solution of tert-butyl(1R,5S)-3-(2-((6-(ethoxycarbonyl)-5-methylpyridin-3-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(Preparation 33, 100 mg, 0.214 mmol) in NH₃/MeOH (15 mL) was heated to90° C. in a sealed vessel for 18 hours. The solution was concentrated invacuo and the residue was treated with 4M HCl/dioxane (20 mL) andstirred at room temperature for 2 hours. solution was concentrated invacuo to afford the title compound as the hydrochloride salt.

Preparation 27((1R,5S)-3-(2-Chloro-5-fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone

To a suspension of(1R,5S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane(Preparation 31, 4 g, 11.7 mmol), cyclopropanecarboxylic acid (2 g, 23.4mmol) and triethylamine (3.5 g, 35.1 mmol) in DMF (40 mL) was added HATU(5.33 g, 14 mmol) at room temperature. After the addition, the reactionwas stirred at room temperature for 30 minutes. The reaction wasconcentrated in vacuo and purified by silica gel column chromatographyeluting with 20% petroleum ether in EtOAc to afford the title compound(2.5 g, 70%). ¹H NMR (400 MHz, CDCl₃): δ ppm 0.80-0.86 (m, 2H),1.01-1.05 (m, 2H), 1.66-2.09 (m, 5H), 3.29-3.34 (m, 2H), 4.23-4.26 (m,1H), 4.37-4.40 (m, 1H), 4.53-4.52 (m, 1H), 4.77-4.78 (m, 1H), 7.94-7.95(m, 1H). MS m/z 311 [M+H]⁺

Preparation 28((1R,5S)-3-(2-Chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone

To a solution of(1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane(Preparation 32, 3.5 g, 15.57 mmol) in DCM (20 mL) was addedtriethylamine (7.86 g, 78 mmol) and cyclopropanecarbonyl chloride (3.26g, 31 mmol) at room temperature. The reaction was stirred at roomtemperature for 1 hour. The reaction was washed with saturated aqueousNaHCO₃ solution (100 mL). The organic layer was collected, dried,concentrated in vacuo and purified by silica gel column chromatographyeluting with 10% MeOH in to afford the title compound (2.5 g, 55%).

MS m/z 293 [M+H]⁺

Preparation 29(1R,5S)-3-(2-Chloropyrimidin-4-yl)-N-ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

To a solution of(1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane_(Preparation32, 170 mg, 0.6173 mmol) in DCM (20 mL) was added triethylamine (125 mg,1.23 mmol) followed by isocyanatoethane (175.4 mg, 2.47 mmol) at 0° C.The reaction was stirred at room temperature for 1 hour beforeconcentrating in vacuo and purifying with silica gel columnchromatography eluting with 20% petroleum ether in EtOAc to afford thetitle compound (184 mg, 100%). MS m/z 296 [M+H]⁺

Preparation 30 Racemic((1R,5S)-3-(2-Chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(2,2-difluorocyclopropyl)methanone

The title compound was prepared according to the method described forPreparation 27 using racemic 2,2-difluorocyclopropane-1-carboxylic acid.MS m/z 329 [M+H]⁺

Preparation 31(1R,5S)-3-(2-Chloro-5-fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane

The title compound was prepared according to the method described forPreparation 25 using tert-butyl(1R,5S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(Preparation 35).

Preparation 32(1R,5S)-3-(2-Chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane

The title compound was prepared according to the method described forPreparation 125 using tert-butyl(1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(Preparation 34) in dioxane.

Preparation 33 tert-Butyl(1R,5S)-3-(2-((6-(ethoxycarbonyl)-5-methylpyridin-3-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

The title compound was prepared according to the method described forPreparation 1 Step 1 using tert-butyl(1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(Preparation 34) and ethyl-5-amino-3-methylpicolinate (Preparation 41).MS m/z 469 [M+H]⁺

Preparation 34 tert-Butyl(1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

To a solution of tert-butyl(1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 36, 11g, 52 mmol) in MeOH (500 mL) was added 2,4-dichloropyrimidine (8.4 g, 57mmol) and TEA (6.7 g, 66 mmol) at 0° C. The reaction was stirred at roomtemperature for 18 hours before concentrating in vacuo. The residue waspurified by silica gel column chromatography eluting with 20% EtOAc inpetroleum ether to afford the title compound as a white solid (12 g,71%).

¹H NMR (400 MHz, CDCl₃): δ ppm 1.48 (s, 9H), 1.63-1.74 (m, 2H), 1.97 (brs, 2H), 3.18 (br s, 2H), 3.38-3.74 (m, 1H), 4.36 (br s, 3H), 6.35 (d,1H), 8.06 (d, 1H). MS m/z 325 [M+H]⁺

Preparation 35 tert-Butyl(1R,5S)-3-(2-chloro-5-fluoropyrimidin-4-v)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

The title compound was prepared according to the method described forPreparation 36 using 2,4-dichloro-5-fluoropyrimidine. The residue waspurified by silica gel column chromatography eluting with 0-100% EtOAcin heptanes. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.38 (s, 9H), 1.62 (d,2H,) 1.76-1.84 (m, 2H), 3.16 (d, 2H), 4.08 (d, 2H), 4.15-4.22 (m, 2H),8.17 (d, 1H).

Preparation 36 tert-Butyl(1R,5S)-3,8-diazabicclo[3.2.1]octane-8-carboxylate

A solution of tert-butyl(1R,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(Preparation 37, 19 g, 63 mmol) in methanol (500 mL) was hydrogenatedover palladium on carbon (4 g) at 50 psi at room temperature for 18hours. The reaction was filtered and the filtrate was concentrated invacuo to afford the title compound as a white solid (13.2 g, 99%).

¹H NMR (400 MHz, MeOH-d₄): δ ppm 1.49 (s, 9H), 1.85-2.02 (m, 4H), 2.65(d, 2H), 2.90 (d, 2H), 4.08 (br s, 2H).

Preparation 37 tert-Butyl(1R,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A solution of (1R,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octane (20 g, 99mmol), ditertbutyldicarboxylate (21 g, 97 mmol) and triethylamine (10 g,99 mmol) in DCM (500 mL) was stirred at room temperature for 18 hours.The reaction was concentrated in vacuo and purified by silica gel columnchromatography eluting with 1% EtOAc in petroleum ether to afford thetitle compound (19 g, 64%).

Preparation 38 5-Amino-N,3-dimethylpicolinamide

Ethyl 5-amino-3-methylpicolinate (Preparation 41, 500 mg, 2.78 mmol) wasdissolved in ethanolic methylamine (30%, 50 mL) and the solution washeated to 100° C. in a sealed vessel for 18 hours. The reaction wascooled, concentrated in vacuo and used directly in the next reaction.

Preparation 39 5-Amino-3-chloro-N-methylpicolinamide

The title compound was prepared according to the method described forPreparation 38 using 5-amino-3-chloro-2-pyridinecarboxylic acid methylester.

Preparation 40 Racemic 2-(5-Sminopyridin-2-yl)propan-1-ol

To a solution of LiAlH₄ (1.16 g, 30.7 mmol) in THE (15 mL) cooled to 0°C. was added racemic methyl 2-(5-aminopyridin-2-yl)propanoate(Preparation 43, 850 mg, 4.72 mmol). The reaction was stirred at roomtemperature for 2 hours before quenching with Na₂SO₄.10H₂O. The reactionwas filtered and the filtrate was concentrated in vacuo to afford thetitle compound (0.72 g, 100%).

¹H NMR (400 MHz, CDCl₃): δ ppm 1.28 (d, 3H), 2.94-3.01 (m, 1H), 3.62 (brs, 1H), 3.78 (m, 1H), 3.85-3.93 (m, 1H), 6.99 (d, 2H), 8.00 (m, 1H).

Preparation 41 Ethyl 5-amino-3-methylpicolinate

A solution of ethyl 3-methyl-5-nitropicolinate (Preparation 53, 28 g,133 mmol) in ethanol (600 mL) was degassed with argon for 15 minutes.10% palladium on carbon (12 g) was added and the reaction washydrogenated under an atmosphere of hydrogen at room temperature for 18hours. The reaction was filtered through a pad of celite and washed withethanol. The filtrate was concentrated in vacuo and the residue purifiedby silica gel column chromatography eluting with 0-2% methanol in DCMfollowed by trituration in hexane to afford the title compound (22 g,92%).

¹H NMR (400 MHz, CDCl₃): δ ppm 1.39 (t, 3H), 3.99 (br s, 2H), 4.38 (q,2H), 6.76 (d, 1H), 7.98 (d, 1H).

The following preparations were prepared according to the methoddescribed by Preparation 41 using the appropriate nitro intermediate asdescribed. The purification method was as described or referred tobelow:

Purification Method 1 (PM1): Silica gel column chromatography elutingwith 25% petroleum ether in EtOAc.

Prepar- ation number Structure Name SM/Data 42

5-amino-N-ethyl-3- methylpicolinamide N-ethyl-3-methyl-5-nitropicolinamide (Preparation 52). PM1. ¹H NMR (400 MHz, CDCl₃): δ ppm1.07 (t, 3H), 2.50 (s, 3H), 3.21 (m, 2H), 5.76 (br s, 2H), 6.71 (d, 1H),7.75 (d, 1H), 8.24 (t, 1H). MS m/z 180 [M + H]⁺ 43

Racemic methyl 2-(5- aminopyridin-2- yl)propanoate Racemic methyl 2-(5-nitropyridin-2-yl)propanoate (Preparation 54) in methanol. Taken ondirectly to the next step. 44

4-amino-N,6- dimethylpicolinamide N,6-dimethyl-4- nitropicolinamide(Preparation 56). ¹H NMR (400 MHz, MeOH-d₄): δ ppm 2.35 (s, 3H), 2.90(s, 3H), 6.50 (d, 1H), 7.05 (d, 1H).

Preparation 45 2-(5-Amino-3-chloropyridin-2-yl)ethan-1-ol

To a solution of methyl 2-(3-chloro-5-nitropyridin-2-yl)acetate(Preparation 58, 4.6 g, 20 mmol) in EtOH/H₂O (50 mL/20 mL) was addedammonium chloride (20 g, 374 mmol) and Fe (8 g, 143 mmol). The reactionwas stirred at room temperature for 3 hours before filtering andconcentrating in vacuo. The residue was purified using silica gel columnchromatography, dissolved in THE (50 mL) and added dropwise to asolution of LiAlH₄ (2.3 g, 55 mmol) in THE (50 mL) at 0° C. The reactionwas stirred at room temperature for 3 hours before quenching withNa₂SO₄.10H₂O at 0° C. The mixture was filtered and the filtrate wasconcentrated in vacuo to afford the title compound as a yellow solid(1.3 g, 46%). MS m/z 173 [M+H]⁺

Preparation 46 2-(5-Amino-3-fluoropyridin-2-yl)ethan-1-ol

The title compound was prepared according to the method described forPreparation 45, 57 and 58 using 2-chloro-3-fluoro-5-nitropyridine. MSm/z 157 [M+H]⁺

Preparation 47 (S)-1-(5-Amino-3-fluoropyridin-2-yl)pyrrolidin-3-ol

To a solution of (S)-1-(3-fluoro-5-nitropyridin-2-yl)pyrrolidin-3-ol(Preparation 59, 250 mg, 1.10 mmol) in EtOH/H₂O (5 mL/2 mL) was addedammonium chloride (233 mg, 4.40 mmol) and Fe (123 mg, 2.20 mmol). Thereaction was stirred at 80° C. for 30 minutes before filtering andconcentrating in vacuo. The residue was purified using silica gel columnchromatography eluting with 10-100% EtOAc in petroleum ether to affordthe title compound (80 mg, 36%).

The following preparations were prepared according to the methoddescribed by Preparation 47 using the appropriate nitro intermediate asdescribed. The purification method was as described or referred tobelow:

Prepa- ration number Structure Name SM/Data 48

(R)-1-(5-amino-3- fluoropyridin-2-yl)pyrrolidin-3- ol (R)-1-(3-fluoro-5-nitropyridin-2-yl)pyrrolidin-3- ol (Preparation 60). Taken on directlyto the next step. 49

1-(5-amino-3-fluoropyridin-2- yl)azetidin-3-ol1-(3-fluoro-5-nitropyridin-2- yl)azetidin-3-ol (Preparation 61). Takenon directly to the next step. 50

2-((5-amino-3-chloropyridin- 2-yl)oxy)ethan-1-ol2-((3-chloro-5-nitropyridin-2- yl)oxy)ethan-1-ol (Preparation 62). Takenon directly to the next step.

Preparation 51 5-Amino-3-fluoro-N-methylpicolinamide

To a solution of 5-((di-[tert-butoxycarbonyl])amino)-3-fluoropicolinicacid (Preparation 65, 750 mg, 2.11 mmol) in DMF (20 mL) was addedtriethylamine (3.2 g, 31.65 mmol), HATU (1.2 g, 3.17 mmol) and MeNH₂.HCl(1.5 g, 22.4 mmol) at 0° C. The reaction was stirred at room temperaturefor 18 hours then concentrated in vacuo. The residue was purified bysilica gel column chromatography eluting with 33% petroleum ether inEtOAc and dissolving in MeOH (20 mL). To the solution was added 4M HClin MeOH (30 mL) and the reaction was stirred at room temperature for 18hours before concentrating in vacuo. The residue was dissolved in MeOH(20 mL) and adjusted to pH 10 by adding 1M aqueous NaHCO₃ solution. Themixture was concentrated in vacuo and added to 10:1 DCM:MeOH (100 mL)and stirred at room temperature for 30 minutes. The mixture was filteredand the filtrate was concentrated in vacuo to afford the title compoundas a yellow solid (480 mg, 80%).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.70-2.71 (d, 3H), 6.25 (s, 2H),6.67-6.71 (dd, 1H), 7.75 (s, 1H), 8.20 (s, 1H).

Preparation 52 N-Ethyl-3-methyl-5-nitropicolinamide

The title compound was prepared according to the method described forPreparation 41 using ethyl 3-methyl-5-nitropicolinate (Preparation 53)and ethylamine at 70° C.

¹H NMR (400 MHz, CDCl₃): δ ppm 1.28 (t, 3H), 2.87 (s, 3H), 3.49 (q, 2H),7.97 (br s, 1H), 8.37 (d, 1H), 9.17 (d, 1H).

Preparation 53 Ethyl 3-methyl-5-nitropicolinate

Sulfuric acid (150 mL) was added slowly to ethanol (600 mL) slowly at 0°C. To this solution was added 2-cyano-3-methyl-5-nitropyridine (15 g, 92mmol) portion-wise and the reaction heated to reflux for 65 hours. Thereaction was cooled, poured into ice-water and extracted into EtOAc. Theorganic layer was collected and the aqueous further washed with EtOAc.The organic extracts were combined, washed with brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified using silicagel column chromatography eluting with 0-30% DCM in hexanes to affordthe title compound (8.5 g, 44%). ¹H NMR (400 MHz, CDCl₃): δ ppm 1.44 (t,3H), 2.67 (s, 3H), 4.50 (q, 2H), 8.39 (d, 1H), 9.29 (d, 1H).

Preparation 54 Racemic Methyl 2-(5-nitropyridin-2-yl)propanoate

A solution of racemic 1-(tert-butyl) 3-methyl2-methyl-2-(5-nitropyridin-2-yl)malonate (Preparation 55, 1.6 g, 5.15mmol) and TFA (15 mL) in DCM (50 mL) was stirred at room temperature for18 hours. The reaction was concentrated in vacuo and treated withtriethylamine before purifying directly by silica gel columnchromatography eluting with 25% EtOAc in petroleum ether to afford thetitle compound (0.99 g, 91%). ¹H NMR (400 MHz, CDCl₃): δ ppm 1.61 (d,3H), 3.72 (s, 3H), 4.10-4.30 (m, 1H), 7.51 (d, 1H), 8.46 (dd, 1H), 9.38(d, 1H).

Preparation 55 Racemic 1-(tert-Butyl) 3-methyl2-methyl-2-(5-nitropyridin-2-yl)malonate

To a solution of 1-(tert-butyl) 3-methyl 2-(5-nitropyridin-2-yl)malonate(PCT Publication No. WO 2007042299, 1.9 g, 6.41 mmol) in DMF (50 mL) wasadded cesium carbonate (4.18 g, 13 mmol) at 0° C. The reaction wasstirred at room temperature for 10 minutes before the addition of MeI(3.64 g, 25.7 mmol) and stirring at room temperature for 3 hours. Thereaction was added water (40 mL) at 10° C. and then extracted with EtOActhree times (3×50 mL). The organic layers were combined, concentrated invacuo and purified by silica gel column chromatography eluting with 25%EtOAc in pentane to afford the title compound (1.6 g, 80%). ¹H NMR (400MHz, CDCl₃): δ ppm 1.47 (s, 9H), 1.89 (s, 3H), 3.80 (s, 3H), 7.71 (d,1H), 8.47 (m, 1H), 9.35 (d, 1H).

Preparation 56 N,6-Dimethyl-4-nitropicolinamide

To a solution of 6-methyl-4-nitro-2-pyridinecarboxylic acid (2 g, 10mmol) in THE (50 mL) was added HOBt (1.77 g, 13.1 mmol), EDCl.HCl (2.30g, 12 mmol), DIPEA (1.90 mL, 10.9 mmol) and methylamine (5.46 mL, 10.9mmol). The reaction was stirred at room temperature for 15 minutesfollowed by reflux for 30 minutes. The reaction was poured intosaturated aqueous NaHCO₃ solution and extracted into EtOAc. The organiclayer was collected dried over sodium sulfate and concentrated in vacuo.The residue was purified using silica gel column chromatography toafford the title compound.

Preparation 57 Methyl 2-(3-chloro-5-nitropyridin-2-yl)acetate

To a solution of 1-(tert-butyl) 3-methyl2-(3-chloro-5-nitropyridin-2-yl)maonate (Preparation 58, 6.6 g, 20 mmol)in DCM (100 mL) was added TFA (100 mL) and the reaction was stirred atroom temperature for 20 hours. The reaction was concentrated in vacuo toafford the title compound as the trifluoroacetate salt (6.8 g, 100%).

Preparation 58 1-(tert-Butyl) 3-methyl2-(3-chloro-5-nitropyridin-2-yl)malonate

To a solution of NaH (6 g, 150 mmol) in DMF (30 mL) was addedtert-butylmethylmalonate (5 g, 28.7 mmol) slowly. The mixture wasstirred at room temperature for 30 minutes before the addition of2,3-dichloro-5-nitropyridine (5 g, 26 mmol) dropwise. The reaction wasstirred at room temperature for 2 hours. The reaction was concentratedin vacuo and purified by silica gel column chromatography to get affordthe title compound (6.6 g, 77%) as red oil.

Preparation 59 (S)-1-(3-Fluoro-5-nitropyridin-2-yl)pyrrolidin-3-ol

To a mixture of NaH (227 mg, 5.68 mmol, 60%) in DME (30 mL) was added(S)-pyrrolidin-3-ol (494 mg, 5.68 mmol) and the reaction was stirred atroom temperature for 1 hour. A solution of2-chloro-4-fluoro-5-nitropyridine (250 mg, 1.42 mmol) in DME (10 mL) wasadded at 10° C. and stirred at room temperature for 1 hour. The reactionwas quenched with water (30 mL) and extracted with EtOAc (100 mL×2). Theorganic layers were combined, concentrated in vacuo and purified bysilica gel column chromatography eluting with 0-50% EtOAc in petroleumether to afford the title compound (250 mg, 77%) as yellow solid.

The following preparations were prepared according to the methoddescribed by Preparation 59 using the appropriate fluoropyridine asdescribed.

Prepa- ration number Structure Name SM/Data 60

(R)-1-(3-fluoro-5-nitropyridin- 2-yl)pyrrolidin-3-ol(R)-pyrrolidin-3-ol. ¹H NMR (400 MHz, DMSO- d₆): δ ppm 1.82-2.05 (m,2H), 3.58-3.92 (m, 4H), 4.34-4.44 (m, 1H), 5.09 (d, 1H), 8.16 (dd, 1H),8.84 (dd, 1H). 61

1-(3-fluoro-5-nitropyridin-2- yl)azetidin-3-ol Azetidinol. ¹H NMR (400MHz, DMSO- d₆): δ ppm 3.98-4.09 (m, 2H), 4.47-4.55 (m, 2H), 4.58-4.69(m, 2H), 5.87 (d, 1H), 8.13-8.21 (m, 1H), 8.75-8.88 (m, 1H). 62

2-((3-chloro-5-nitropyridin-2- yl)oxy)ethan-1-ol Ethane-1,2-diol. Takenon directly to the next step.

Preparation 63 Methyl4-((tert-butoxycarbonyl)amino)-6-(hydroxymethyl)picolinate

To a solution of dimethyl4-((tert-butoxycarbonyl)amino)pyridine-2,6-dicarboxylate (Preparation64, 300 mg, 0.967 mmol), in DCM (2 mL) and MeOH (1 mL) at 0° C. wasadded sodium borohydride (38 mg, 0.966 mmol). The reaction was stirredat this temperature for 30 minutes, further sodium borohydride (17 mg,0.483 mmol) was added and the reaction stirred at room temperature for18 hours. The reaction was quenched by the addition of 1:1 brine:waterand extracted into EtOAc five times. The organic layers were combined,dried over sodium sulfate and concentrated in vacuo to afford the titlecompound as a white solid (232 mg, 85%). MS m/z 281 [M−H]⁻

Preparation 64 Dimethyl4-((tert-butoxycarbonyl)amino)pyridine-2,6-dicarboxylate

To a solution of dimethyl 4-bromopyridine-2,6-dicarboxylate (2.4 g, 8.76mmol) in dioxane (30 mL) was added tert-butylcarbamate (1.13 g, 9.63mmol), Pd₂(dba)₃ (246 mg, 0.263 mmol), xantphos (207 mg, 0.350 mmol) andcesium carbonate (5.7 g, 17.5 mmol). The reaction was degassed withargon and heated to 85° C. for 18 hours. The reaction was cooled,concentrated in vacuo and purified using silica gel columnchromatography eluting with 20% EtOAc in heptanes to afford the titlecompound (1.2 g, 44%).

¹H NMR (400 MHz, CDCl₃): δ ppm 1.55 (s, 9H), 4.05 (s, 6H), 7.30 (d, 1H),8.35 (d, 1H).

Preparation 65 5-((di-[tert-Butoxycarbonyl]amino)-3-fluoropicolinic acid

To a solution of ethyl5-((di-[tert-butoxycarbonyl])amino)-3-fluoropicolinate (Preparation 66,3.3 g, 8.59 mmol) in THF:water (46 mL, 15:8) was added LiOH (0.72 g,17.12 mmol) at room temperature. The reaction was stirred at roomtemperature for 4 hours. The reaction was acidified to pH 3 by theaddition of citric acid at 0° C. and extracted with ethyl acetate (50mL×2). The combined organic layers were concentrated in vacuo to affordthe title compound as a white solid (2.6 g, 86%).

MS m/z 357 [M+H]⁺

Preparation 66 Ethyl5-((di-[tert-butoxycarbonyl]amino)-3-fluoropicolinate

To a solution of di-[tert-butylcarbamate]-(6-bromo-5-fluoropyridin-3-yl) (Preparation 67, 3.7 g, 9.46mmol) in ethanol (100 mL) was added Pd(OAc)₂ (1.6 g, 7.53 mmol), DPPP(3.12 g, 7.56 mmol) and triethylamine (5.4 g, 53.46 mmol). The reactionwas heated to 60° C. under an atmosphere of carbon monoxide at 50 psifor 18 hours. The reaction was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with 10% EtOAc in petroleum ether to afford thetitle compound (3.3 g, 90%).

Preparation 67 di-[tert-Butyl carbamate]-(6-bromo-5-fluoropyridin-3-yl)

To a solution of 6-bromo-5-fluoro-3-pyridinamine (2.6 g, 13.6 mmol) inTHE (100 mL) was added ditertbutyldicarbonate (8.81 g, 40.8 mmol), DIPEA(5.26 g, 40.8 mmol) and DMAP (83.2 mg, 0.68 mmol) at room temperature.The reaction was heated to reflux for 4 hours. The reaction wasconcentrated in vacuo and purified by silica gel column chromatographyeluting with 10% EtOAc in petroleum ether to afford the title compoundthat was taken on directly to the next step (3.7 g, 56%).

Preparation 68 (S)-2,2-Difluorocyclopropane-1-carboxylic acid

To a solution of (S)-1-phenylethyl(S)-2,2-difluorocyclopropane-1-carboxylate (Preparation 70, 3.67 g, 16.2mmol) in MeOH (48 mL) was added 1N NaOH (48 mL, 48 mmol) and thereaction was stirred at room temperature for 1.5 hours. The reaction wasconcentrated in vacuo, acidified to pH=5.8 using 12N HCl (aq) andextracted into nBuOH. The organic layer was collected and concentratedin vacuo to afford the title compound (1.5 g, 76%). ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.90 (m, 2H), 2.65 (m, 1H).

Preparation 69 (R)-2,2-Difluorocyclopropane-1-carboxylic acid

The title compound was prepared according to the method described forPreparation 68 using(S)-1-phenylethyl(R)-2,2-difluorocyclopropane-1-carboxylate (Preparation71).

Preparations 70 and 71(S)-1-Phenylethyl(S)-2,2-difluorocyclopropane-1-carboxylate and(S)-1-phenylethyl(R)-2,2-difluorocyclopropane-1-carboxylate

To a solution of 2,2-difluoro-cyclopropanecarboxylic acid (4.02 g, 33mmol) in DCM (140 mL) was added DCC (8.16 g, 39 mmol) followed by DMAP(403 mg, 3.30 mmol) and the reaction was stirred for 10 minutes.(S)-1-phenylethan-1-ol (4.83 g, 39 mmol) was added and the reactionstirred at room temperature for 72 hours. The reaction was filtered,concentrated in vacuo and purified using silica gel columnchromatography eluting with 0-5% EtOAc to afford the title compounds asa mixture of diastereomers. The diastereomers were separated usingchromatography as described below: Kromasil Silica 10 um, 4.6×250 mm;run time 14 minutes; 1.0 mL/min; eluting with 3% MTBE in heptanes.

Peak 1: Rt=5.34 minutes;(S)-1-phenylethyl(S)-2,2-difluorocyclopropane-1-carboxylate (Preparation70). ¹H NMR (400 MHz, CDCl₃): δ ppm 1.61 (d, 3H), 1.74-1.79 (m, 1H),2.06-2.12 (m, 1H), 2.45-2.53 (m, 1H), 5.95-6.00 (m, 1H), 7.33-7.42 (m,5H).

Peak 2: Rt=6.22 minutes;(S)-1-phenylethyl(R)-2,2-difluorocyclopropane-1-carboxylate (Preparation71). ¹H NMR (400 MHz, CDCl₃): δ ppm 1.61 (d, 3H), 1.74-1.79 (m, 1H),2.06-2.12 (m, 1H), 2.45-2.53 (m, 1H), 5.95-6.00 (m, 1H), 7.33-7.42 (m,5H).

Preparation 72 (1R,2R)-2-Cyanocyclopropane-1-carboxylic acid

To a solution of benzyl (1R,2R)-2-cyanocyclopropane-1-carboxylate(Preparation 74, 100 mg, 0.5 mmol) in anhydrous THE (10 mL) was addedwet Pd/C (10 mg). The reaction was degassed, then stirred at roomtemperature under a balloon of hydrogen for 1 hour. The reaction wasfiltered and the filtrate concentrated in vacuo to afford the titlecompound as a white solid that was used directly in the next step (56mg, 100%).

Preparation 73 (1S,2S)-2-Cyanocyclopropane-1-carboxylic acid

The title compound was prepared according to the method described forPreparation 72 using benzyl (1S,2S)-2-cyanocyclopropane-1-carboxylate(Preparation 75).

Preparations 74 and 75 Benzyl(1R,2R)-2-Cyanocyclopropane-1-carboxylateand Benzyl(1S,2S)-2-Cyanocyclopropane-1-carboxylate

To a solution of trans-racemic ethyl 2-cyanocyclopropane-1-carboxylate(Preparation 77, 24.7 g, 0.17 mol) in THE (400 mL) and water (200 mL)was added lithium hydroxide (14.9 g, 0.35 mol) and the reaction wasstirred at room temperature for 2 hours. The reaction was diluted withwater (20 mL) and extracted with DCM (2×30 mL). The aqueous layer wasacidified to pH 2 with 1M HCl and extracted into EtOAc three times(3×400 mL). The combined organic layers were washed with brine, driedover sodium sulfate and concentrated in vacuo. The residue wasrecrystallized from ether to afford the carboxylic acid. To a portion ofthe acid (8 g, 0.072 mol) in DMF (150 mL) was added cesium carbonate(25.8 g, 0.35 mol) followed by benzyl bromide (13.6 g, 0.08 mol) and thereaction was stirred at room temperature for 18 hours. The reaction wasdiluted with water (300 mL) and extracted with EtOAc three times (3×400mL). The combined organic layers were washed with brine, dried oversodium sulfate and concentrated in vacuo. The residue was purified bysilica gel column chromatography eluting with 10-70% EtOAc in petroleumether to afford the title compound as the trans-racemate (13.6 g, 94%).

The trans-racemate was separated by chiral chromatography as describedbelow: Column: OD 300 mm×50 mm×10 μm.

Mobile phase: A: Supercritical CO₂, B: EtOH (0.1% NH₃H₂O), A:B=90:10;Flow rate: 180 mL/min

Preparation 74: Benzyl (1S,2S)-2-cyanocyclopropane-1-carboxylate (5.80g, 43%) Peak 1, Rt=3.61 minutes; ¹H NMR (400 MHz, CDCl₃): δ ppm1.50-1.56 (m, 2H), 1.96-1.99 (m, 1H), 2.29-2.32 (m, 1H), 5.16 (s, 2H),7.35-7.41 (m, 5H).

Preparation 75: Benzyl (1R,2R)-2-cyanocyclopropane-1-carboxylate (5.82g, 43%) Peak 2, Rt=3.87 minutes; ¹H NMR (400 MHz, CDCl₃): δ ppm1.50-1.56 (m, 2H), 1.96-1.98 (m, 1H), 2.30-2.32 (m, 1H), 5.16 (s, 2H),7.35-7.41 (m, 5H).

Preparations 76 and 77 cis-racemic and trans-racemic Ethyl2-cyanocyclopropane-1-carboxylate

Acrylonitrile (70 g, 1.32 mol) was stirred under reflux as ethyldiazoacetate (70 g, 0.614 mol) was added portion wise over period of 2.5hours. After completion of the addition, the mixture was stirred atreflux for an additional 1.5 hours, before removing the excessacrylonitrile by distillation. The reaction was then heated to 125-130°C. and maintained there until nitrogen evolution ceased and the reactionwas heated to 160-170° C. for 1 hour before cooling to room temperatureunder nitrogen. The reaction was distilled under vacuum and the productpurified by silica gel column chromatography eluting with 10-50% EtOAcin petroleum ether afford trans-racemic ethyl2-cyanocyclopropane-1-carboxylate as the first eluting compound (24 g,28%) and cis-racemic ethyl 2-cyanocyclopropane-1-carboxylate as thesecond eluting compound (17 g, 20%).

Preparation 76

¹H NMR (400 MHz, CDCl₃): δ ppm 1.30 (m, 3H), 1.42 (m, 1H), 1.67 (m, 1H),1.82 (m, 1H), 2.10 (m, 1H), 4.23 (m, 2H)

Preparation 77

¹H NMR (400 MHz, CDCl₃): δ ppm 1.28 (m, 3H), 1.42 (m, 1H), 1.66 (m, 1H),1.82 (m, 1H), 2.10 (m, 1H), 4.23 (m, 2H); MS m/z 140 [M+H]⁺

Preparation 78 N-(2-Cyanoethyl)-1H-imidazole-1-carboxamide

To a solution of CDI (250 mg, 1.56 mmol) and triethylamine (236 mg, 2.34mmol) in anhydrous THE (15 mL) was added a solution of 2-cyanoethylamine(100 mg, 0.78 mmol) in anhydrous THE (5 mL) at 0° C. and the reactionwas stirred at room temperature for 18 hours The reaction wasconcentrated in vacuo and purified by silica gel column chromatographyeluting with EtOAc to afford the title compound as a colourless oil (44mg, 34%). ¹H NMR (400 MHz, CDCl₃): δ ppm 2.79 (t, 2H), 3.47 (q, 2H),7.12 (s, 1H), 7.50 (s, 1H), 7.66 (br s, 1H), 8.39 (s, 1H).

Preparation 79 N-(Cyanomethyl)-1H-imidazole-1-carboxamide

To a solution of aminoacetonitrile bisulfate (436 mg, 2.75 mmol) and1,1′-carbonyldiimidazole (500 mg, 3.0 mmol) in acetonitrile (3 mL) wasadded N,N-dimethylformamide (1 mL) and the reaction stirred at roomtemperature in a sealed vessel for 18 hours. The residue wasconcentrated in vacuo, taken up in DCM and filtered. The filtrate waspurified using silica gel column chromatography eluting with 0-10% MeOHin DCM to afford the title compound.

¹H NMR (400 MHz, CDCl₃): δ ppm 3.50 (s, 2H), 7.18 (d, 1H), 7.30 (d, 1H),7.75 (s, 1H).

Preparation 80 N-Ethyl-1H-imidazole-1-carboxamide

Ethylamine hydrochloride (1.78 g, 21 mmol) and CDI (4.20 g, 25 mmol) wasstirred at room temperature in MeCN (20 mL) for 3 hours. The reactionwas diluted with DCM, filtered and concentrated in vacuo. The residuewas further diluted with DCM, filtered, and purified using silica gelcolumn chromatography eluting with 0-10% MeOH in DCM to afford the titlecompound.

¹H NMR (400 MHz, CDCl₃): δ ppm 1.88 (t, 3H), 3.50 (m, 2H), 6.35 (br s,1H), 7.10 (d, 1H), 7.40 (d, 1H), 8.20 (s, 1H).

Preparation 81 N-Isopropyl-1H-imidazole-1-carboxamide

The title compound was prepared according to the method described forPreparation 80 using isopropylamine hydrochloride with DMF (1 mL). Theresidue was suspended in EtOAc, filtered, the filtrate washed withbrine, concentrated in vacuo and taken directly on to the next step.

¹H NMR (400 MHz, CDCl₃): δ ppm 1.20 (m, 6H), 4.10 (m, 1H), 6.95 (s, 1H),7.50 (d, 1H), 7.80 (d, 1H), 7.80 (m, 1H), 8.20 (d, 1H).

Preparation 82 N-(2,2,2-Trifluoroethyl)-1H-imidazole-1-carboxamide

The title compound was prepared according to the method described forPreparation 80 using 2,2,2-trifluoroethan-1-amine hydrochloride withDMF. ¹H NMR (400 MHz, CDCl₃): δ ppm 4.00 (m, 2H), 7.00 (d, 1H), 7.60 (d,1H), 8.25 (s, 1H), 9.00 (br s, 1H).

Preparation 83 5-Amino-N-propyl-1H-pyrazole-3-carboxamide hydrochloride

A solution of 1-(tert-butyl) 3-ethyl5-amino-1H-pyrazole-1,3-dicarboxylate (Preparation 84, 7.5 g, 29 mmol)in propylamine (40 mL) was heated to reflux for 48 hours. The reactionwas cooled, concentrated in vacuo and dissolved in DCM (20 mL). 4N HClin dioxane (20 mL) was added and the reaction stirred at roomtemperature for 2 hours. The resulting solid was filtered, washed withtert-butyl ether and dried. The solid was recrystallised from 2:1EtOAc:IPA with decolourising charcoal to afford the title compound asthe hydrochloride salt (5.1 g, 85%).

¹H NMR (400 MHz, MeOH-d₄): δ ppm 0.95 (t, 3H), 1.60 (m, 2H), 3.30 (m,4H), 5.90 (br s, 1H).

Preparation 84 1-(tert-Butyl) 3-ethyl5-amino-1H-pyrazole-1,3-dicarboxylate

To a solution of tert-butyl(Z)-2-(1-cyano-2-ethoxy-2-oxoethylidene)hydrazine-1-carboxylate(Preparation 85, 10.5 g, 41 mmol) in acetonitrile (150 mL) was addedtriethylamine (17.4 mL, 123 mmol) and the reaction was stirred at roomtemperature for 3 hours. The reaction was concentrated in vacuo andpurified using silica gel column chromatography eluting with from 20-80%EtOAc in heptanes.

¹H NMR (400 MHz, CDCl₃): δ ppm 1.40 (t, 3H), 1.60 (s, 9H), 4.40 (q, 2H),5.40 (br s, 2H), 5.95 (s, 1H).

Preparation 85 tert-Butyl(Z)-2-(1-cyano-2-ethoxy-2-oxoethylidene)hydrazine-1-carboxylate

To a solution of sodium ethylate (21% solution in EtOH, 51 mL, 137 mmol)in diethylether (30 mL) was added a solution of diethyl oxalate (20 g,140 mmol) in diethylether (80 mL) dropwise over 15 minutes at 0° C.followed by stirring at this temperature for 1 hour. Acetonitrile (7.15mL, 137 mmol) was added slowly and the reaction stirred at roomtemperature for 18 hours. The resulting precipitate was filtered, washedwith 1:1 ether:ethanol and dried under vacuum. The solid (8.7 g, 53mmol) was dissolved in ethanol (25 mL) and acetic acid (3.2 g, 53 mmol)and cooled to 0° C. tert-Butyl hydrazinecarboxylate (7.75 g, 59 mmol)was added and the reaction stirred at 0° C. for 1 hour followed by roomtemperature for 18 hours. The reaction was concentrated in vacuo andpartitioned between EtOAc and saturated aqueous sodium carbonatesolution. The organic layer was collected, dried over sodium sulfate andconcentrated in vacuo to afford the title compound as an orange solid(10.5 g, 77%).

Preparation 86 6-Aminoimidazo[1,2-a]pyridine-2-carboxamide

To a solution of ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate(Preparation 87, 2 g, 0.0074 mol) in MeOH (30 mL) was added ammonia (3g, 0.044 mol) and the reaction was heated to 100° C. in a sealed vesselfor 24 hours. The reaction was cooled and concentrated in vacuo toafford the title compound (1.9 g, 90%).

Preparation 87 Ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate

To a solution of 2-amino-5-bromopyridine (5 g, 0.029 mol) in ethanol(180 mL) was added ethyl 3-bromo-2-oxopropanoate (5.64 g, 0.029 mol) andNaHCO₃ (4.86 g, 0.058 mol) and the reaction was heated to reflux for 18hours. The reaction was cooled, concentrated in vacuo and partitionedbetween EtOAc and saturated aqueous sodium carbonate solution. Theorganic layer was collected, washed with brine, dried over magnesiumsulfate and concentrated in vacuo. The residue was purified using silicagel column chromatpgraphy eluting with 30% EtOAc in petroleum ether toafford the title compound (4.2 g, 45%).

Preparation 88(S)-N-((1S,5S)-3-(2-Chloro-5-fluoropyrimidin-4-yl)-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-2,2-difluorocyclopropane-1-carboxamide

The title compound was prepared according to the method described forPreparation 27 usingracemic-(5-amino-3-(2-chloro-5-fluoropyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol(Preparation 99) and (S)-2,2-difluorocyclopropane-1-carboxylic acid(Preparation 68) with DIPEA in DCM. The racemic residue was purifiedusing silica gel column chromatography eluting with 50-100% EtOAc inheptanes. The second, more polar eluting isomer was collected as thetitle compound.

MS m/z 363 [M+H]⁺

Preparation 89Racemic-(1R,2R)-N-(3-(2-Chloro-5-fluoropyrimidin-4-yl)-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-2-cyanocyclopropane-1-carboxamide

The racemic title compound was prepared according to the methoddescribed for Preparation 27 usingracemic-(5-amino-3-(2-chloro-5-fluoropyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol(Preparation 99) and (1R,2R)-2-cyanocyclopropane-1-carboxylic acid(Preparation 72) with DIPEA in DCM. The residue was purified usingsilica gel column chromatography eluting with 50-100% EtOAc in heptanes.MS m/z 352 [M+H]⁺

Preparation 90(1S,5R,6R)-3-(5-Fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-aminehydrochloride

To a solution of tert-butyl((1S,5R,6R)-3-(2-chloro-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo-[3.1.0]hexan-1-yl)carbamate(Preparation 94, 1 g, 2.91 mmol) in isopropanol (10 mL) was added1-methyl-1H-pyrazol-4-ylamine hydrochloride (506 mg, 3.79 mmol) and thereaction was heated to 140° C. under microwave irradiation for 1 hour.The resulting solid was filtered and dried to afford the title compoundas the hydrochloride salt (991 mg, 86%). MS m/z 304 [M+H]+

The following preparations were prepared according to the methoddescribed by Preparation 90 or Preparation 1 using the appropriatehalide and the appropriate amine as described below. The compounds wereisolated as the hydrochloride salts unless otherwise specified.

Deprotection Method B: The Boc-protected intermediate was dissolved inDCM, treated with TFA and stirred at room temperature for 18 hours. Thereaction was basified to pH=10 by the addition of triethylamine. Thesolution was concentrated in vacuo and purified by silica gel columnchromatography eluting with 10% MeOH in DCM.

Prepa- ration number Structure Name SM/Data 91

(1R,5S,6S)-3-(5-fluoro-2- ((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6- methyl-3- azabicyclo[3.1.0]hexan-1- aminehydrochloride tert-butyl ((1R,5S,6S)-3-(2- chloro-5-fluoropyrimidin-4-yl)-6-methyl-3- azabicyclo[3.1.0]hexan-1- yl)carbamate (Preparation 96)and 1-methyl-1H- pyrazol-4-ylamine hydrochloride. MS m/z 304 [M + H]⁺ 92

2-((5-((4-((1S,5R,6R)-1- amino-6-methyl-3- azabicyclo[3.1.0]hexan-3-yl)-5-methylpyrimidin-2- yl)amino)pyridin-2- yl)oxy)ethan-1-oltert-butyl ((1S,5R,6R)-3-(2- chloro-5-methylpyrimidin-4- yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1- yl)carbamate (Preparation 97) and2-[(5-amino-2- pyridinyl)oxy]-ethanol. Taken on directly to the nextstep. 93

(1S,5R,6R)-3-(5-fluoro-2- ((1-(oxetan-3-yl)-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)-6- methyl-3- azabicyclo[3.1.0]hexan-1- aminetert-butyl ((1R,5S,6S)-3-(2- chloro-5-fluoropyrimidin-4- yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1- yl)carbamate (Preparation 96) and1-(oxetan-3-yl)-1H- pyrazol-4-amine (Preparation 123) with deprotectionmethod B.

Preparation 94 tert-Butyl((1S,5R,6R)-3-(2-chloro-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate

To a solution of tert-butyl((1S,5R,6R)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate(Preparation 101, 1.8 g, 8.50 mmol) and triethylamine (1.7 g, 16.8 mmol)in MeOH (100 mL) was added 2,4-dichloro-5-fluoropyrimidine (1.5 g, 9.03mmol), and the reaction was stirred at room temperature for 18 hours.The reaction was concentrated in vacuo and purified directly usingsilica gel column chromatography eluting with 20% EtOAc in petroleumether to afford the title compound as a white solid (2 g, 69%). ¹H NMR(400 MHz, DMSO-d₆): δ ppm 0.98 (d, 3H), 1.39 (m, 1H), 1.45 (br s, 9H),1.80 (m, 1H), 3.67-4.17 (m, 4H), 5.05 (m, 1H), 7.86 (d, 1H). MS m/z 343[M+H]⁺ Chiral Analytical Column: Chiralpak AD-3 150 mm×4.6 mm I.D., 3μm; Retention Time: 3.83 minutes; 100% ee. Mobile phase: Methanol (0.05%Ethanolamine) in CO₂ from 5% to 40%, Flow rate: 2.5 mL/min

Preparation 95 and 95AN-((1S,5R,6R)-3-(2-Chloro-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicclo[3.1.0]hexan-1-yl)cyclopropanecarboxamideandN-((1R,5S,6S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamide

The title compounds were prepared as a trans-racemic mixture accordingto the method described by Preparation 94 usingtrans-racemic-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)cyclo-propanecarboxamide(Preparation 102). GCMS Rt=5.91 minutes MS m/z 310[M]N-((1S,5R,6R)-3-(2-chloro-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamidemay also be prepared as the single enantiomer according to the methodsdescribed by Preparations 94 and 102 usingN-((1S,5R,6R)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamide(Preparation 107A).

Preparation 96 tert-Butyl((1R,5S,6S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate

The title compound was prepared according to the methods described forPreparations 105, 101 and 94 using(1R,5S,6S)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-amine(Preparation 110).

Preparation 97 tert-Butyl((1S,5R,6R)-3-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate

The title compound was prepared according to the method described forPreparation 94 using tert-butyl((1S,5R,6R)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate(Preparation 101) and 2,4-dichloro-5-methylpyrimidine. LCMS Rt=0.90minutes; MS m/z 339 [M+H]⁺

Preparation 98Racemic-N-(3-(2,5-Dichloropyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamide

The title compound was prepared according to the method described forPreparation 94 usingracemic-N-(3-azabicyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamide(Preparation 103) and 2,4,5-trichloropyrimidine. The residue waspurified using silica gel column chromatography eluting with 10% MeOH inDCM.

Preparation 99Racemic-(5-Amino-3-(2-chloro-5-fluoropyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol

To a solution of racemic-tert-butyl(5-(((tert-butyldimethylsilyl)oxy)methyl)-3-(2-chloro-5-fluoropyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)carbamate(Preparation 100, 1.25 g, 2.64 mmol) in DCM (25 mL) was added TFA (5 mL)and the reaction was stirred at 0° C. for 30 minutes followed by roomtemperature for 3 hours. The reaction was quenched with saturatedaqueous NaHCO₃ solution, basified to pH=12 with solid NaOH and extractedinto DCM. The organic layer was collected, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with 0-5% MeOH in DCM to afford the titlecompound (200 mg, 30%).

LCMS Rt=0.49 minutes; MS m/z 261 [M³⁷Cl+H]⁺

Preparation 100 Racemic-tert-Butyl(5-(((tert-butyldimethylsilyl)oxy)methyl)-3-(2-chloro-5-fluoropyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)carbamate

The title compound was prepared according to the method described forPreparation 94 using racemic-tert-butyl(5-(((tert-butyldimethylsilyl)oxy)methyl)-3-azabicyclo[3.1.0]hexan-1-yl)carbamate(Preparation 104) and 2,4-dichloro-5-fluoropyrimidine. MS m/z 473 [M+H]⁺

Preparation 101 tert-Butyl((1S,5R,6R)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate

To a solution of tert-butyl((1S,5R,6R)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate(Preparation 105, 3.4 g, 0.326 mmol) in MeOH (200 mL) was added Pd(OH)₂(20%, 3 g) and the reaction was hydrogenated under 50 psi of hydrogen atroom temperature for 2 days. The reaction was filtered and concentratedin vacuo to afford the title compound give (2.3 g, 100%).

The following preparations were prepared according to the methoddescribed by Preparation 101 or Preparation 1 using the appropriatebenzyl protected intermediate as described below:

Prepa- ration number Structure Name SM/Data 102

 

N-((1S,5R,6R)-6-methyl- 3-azabicyclo[3.1.0]hexan- 1-yl)cyclopropane-carboxamide and N- ((1R,5S,6S)-6-methyl-3- azabi-cyclo[3.1.0]hexan-1-yl)cyclopropane- carboxamide GCMS Rt = 3.64 minutes MS m/z 181 [M]Trans-racemic 3-benzyl-6- methyl-3-azabi- cyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamide (Preparation 107). Isolated as the trans-racemic mixture. 103

Racemic-N-(3-azabi- cyclo[3.1.0]hexan-1- yl)cyclo- propanecarboxamideRacemic-N-(3-benzyl-3- azabicyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamide (Preparation 108) with Pd/C. Taken ondirectly to the next step. 104

Racemic-tert-butyl (5- (((tert-butyldimethyl- silyl)oxy)methyl)-3-azabicyclo[3.1.0]hexan-1- yl)carbamate Racemic-tert-butyl (3-benz-yl-5-(((tert-butyldimeth- ylsilyl)oxy)methyl)-3-azabicyclo[3.1.0]hexan-1- yl)carbamate (Preparation 106). Taken ondirectly to the next step.

Preparation 105 tert-Butyl((1S,5R,6R)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate

To a solution of(1S,5R,6R)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-amine(Preparation 109, 2.5 g, 0.0123 mol) and triethylamine (2.5 g, 0.0247mmol) in DCM (50 mL) was added ditertbutyldicarbonate (2.6 g, 0.0130mmol) and the reaction was stirred at room temperature for 18 hours. Thereaction was filtered and the filtrate was purified directly by silicagel column chromatography eluting with 10% EtOAc in petroleum ether toafford the title compound as a yellow oil (3.4 g, 91%).

Preparation 106 Racemic-tert-Butyl(3-benzyl-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-azabicclo[3.1.0]hexan-1-yl)carbamate

The title compound was prepared according to the method described forPreparation 105 usingracemic-3-benzyl-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-azabicyclo[3.1.0]hexan-1-amine(Preparation 111) in TBME. MS m/z 433 [M+H]⁺

Preparation 107N-((1S,5R,6R)-3-Benzyl-6-methyl-3-azabicclo[3.1.0]hexan-1-yl)cyclopropanecarboxamideandN-((1R,5S,6S)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamide

To a solution oftrans-racemic-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-amine(Preparations 109 and 110, 700 mg, 3.46 mmol) in DCM (15 mL) was addedDIPEA (1.20 mL, 6.92 mmol) followed by cyclopropylcarbonyl chloride (362mg, 3.46 mmol) and the reaction was stirred at room temperature for 2hours. The reaction was concentrated in vacuo and purified directlyusing silica gel column chromatography eluting with 10-100% EtOAc inheptanes to afford the trans-racemic mixture of the title compounds (400mg, 43%).

N-((1S,5R,6R)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamidemay also be prepared as the single enantiomer according to thispreparation using(1S,5R,6R)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-amine(Preparation 667C).

Preparation 108Racemic-N-(3-Benzyl-3-azabicyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamide

The title compound was prepared according to the method described byPreparation 107 using racemic-3-benzyl-3-azabicyclo[3.1.0]hexan-1-amine(Tetrahedron L., (2003), 44 (12), 2485-2487) and triethylamine withcyclopropylcarbonyl chloride. The residue was purified directly usingsilica gel column chromatography eluting with 10% MeOH in DCM.

Preparations 109 and 110(1S,5R,6R)-3-Benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-amine and(1R,5S,6S)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-amine

To a solution of (Z)-2-(benzyl(but-2-en-1-yl)amino)acetonitrile(Preparation 112, 64 g, 0.32 mol) in anhydrous THE (2 L) under nitrogenwas added Ti(O^(i)Pr)₄ (300 g, 1.05 mol) followed by cyclohexylmagnesiumchloride (2M solution in ether, 800 mL, 1.6 mol) dropwise at 20-30° C.over 1.5 hours. The reaction was then stirred at room temperature for 2hours. The reaction was quenched by the addition of 10% aqueous NaOH (1L) and stirred for 1 hour before filtering and concentrating in vacuo.The residue was dissolved in DCM (6 L), washed with water (2 L), driedover sodium sulfate and concentrated in vauco. The residue was purifiedusing silica gel column chromatography eluting with 10% MeOH in DCM toafford the trans-racemic mixture of the title compounds (827 g, 36%).

¹H NMR (400 MHz, CDCl₃): δ ppm 1.07-1.08 (m, 1H), 1.18-1.21 (m, 1H),1.25-1.28 (d, 3H), 2.54-2.56 (d, 1H), 2.76-2.81 (m, 2H), 3.05-3.07 (d,1H), 3.55 (s, 2H), 7.21-7.31 (m, 5H). MS m/z 203 [M+H]⁺

The trans-racemic compound may be separated into its enantiomers usingchiral chromatography as described below:

Chiral column: IC 300 mm×50 mm×10 μm; Mobile phase: A: SupercriticalCO₂, B: MeOH (with 0.1% aqueous ammonia), A:B=75:25 at 200 mL/min

Chiral LCMS QC:

Chiralpak Pheno Lux Cellulose-2; 150 mm×4.6 mm I.D. 5 μm; mobile phaseMeOH (0.05% ethanolamine) in CO₂ from 5-60%; flow rate 3 mL/min.

(1R,5S,6S)-3-Benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-amine

First eluting isomer: Rt=6.78 minutes, 89.9% ee. ¹H NMR (400 MHz,CDCl₃): δ ppm 1.08-1.11 (m, 1H), 1.16-1.22 (m, 1H), 1.26 (m, 3H) 2.54(d, 1H), 2.70-2.84 (m, 2H), 3.05 (d, 1H), 3.59 (s, 2H), 7.23-7.30 (m,5H).

(1S,5R,6R)-3-Benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-amine

Second eluting isomer: Rt=6.10 minutes, 99.4% ee. ¹H NMR (400 MHz,CDCl₃): δ ppm 1.05-1.13 (m, 1H), 1.20 (m, 1H), 1.26 (m, 3H), 2.53 (m,1H), 2.71-2.84 (m, 2H), 3.05 (d, 1H), 3.58 (s, 2H), 7.25-7.30 (m, 5H).

Preparation 111Racemic-3-Benzyl-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-azabicyclo[3.1.0]hexan-1-amine

The title compound was prepared according to the method described forPreparations 109 and 110 using2-(benzyl(2-(((tert-butyldimethylsilyl)oxy)methyl)allyl)amino)acetonitrile(Preparation 114).

Preparation 112 (Z)-2-(Benzyl(but-2-en-1-yl)amino)acetonitrile

To a solution of 2-(benzyl(but-2-yn-1-yl)amino)acetonitrile (Preparation113, 100 g, 0.5 mol) in MeOH (2000 mL) was added Lindlar catalyst (10 g)and the reaction was stirred at 30° C. under a balloon of hydrogen for24 hours. The reaction was filtered and concentrated in vacuo to affordthe title compound. ¹H NMR (400 MHz, CDCl₃): δ ppm 1.72-1.74 (m, 3H),3.26-3.27 (m, 2H), 3.45 (s, 2H), 3.69 (s, 2H), 5.45-5.48 (m, 1H),5.73-5.77 (m, 1H), 7.29-7.39 (m, 5H).

Preparation 113 2-(Benzyl(but-2-yn-1-yl)amino)acetonitrile

To a solution of 2-(benzylamino)acetonitrile (Preparation 115, 666 g,4.56 mol) in MeCN (11 L) was added 1-bromobut-2-yne (600 g, 4.51 mol)and potassium carbonate (1365 g, 14 mol) and the reaction was heated to40° C. for 18 hours. The reaction was filtered, concentrated in vacuoand purified using silica gel column chromatography eluting with 3-10%EtOAc in petroleum ether to afford the title compound as a yellow oil(700 g, 77%). ¹H NMR (400 MHz, CDCl₃): δ ppm 1.72-1.74 (m, 3H),3.25-3.27 (d, 2H), 3.45 (s, 2H), 3.69 (s, 2H), 7.29-7.39 (m, 5H).

Preparation 1142-(Benzyl(2-(((tert-butyldimethylsilyl)oxy)methyl)allyl)amino)acetonitrile

The title compound was prepared according to the method described byPreparation 113 using((2-(bromomethyl)allyl)oxy)(tert-butyl)dimethylsilane and2-(benzylamino)acetonitrile (Preparation 115) at 75° C. for 6 hours. ¹HNMR (400 MHz, CDCl₃): b ppm 0.00 (s, 6H), 0.80 (s, 9H), 3.15 (s, 2H),3.35 (s, 2H), 3.60 (s, 2H), 4.10 (s, 2H), 5.10 (m, 1H), 5.20 (m, 1H),7.20-7.40 (m, 5H).

Preparation 115 2-(Benzylamino)acetonitrile

To a solution of benzylamine (1250 g, 11.68 mol) and DIPEA (2878 g,22.31 mol) in acetonitrile (13 L) was added 2-bromoacetonitrile (1340 g,11.17 mol) and the reaction was stirred at room temperature for 3 hours.The reaction was concentrated in vacuo and dissolved in DCM (2.5 L). Thesolution was washed with water (1.5 L×2), concentrated in vacuo andpurified using silica gel column chromatography eluting with 10-30%EtOAc in petroleum ether (1600 g, 94%).

¹H NMR (400 MHz, CDCl₃): δ ppm 3.57 (s, 2H), 3.94 (s, 2H), 7.35-7.37 (m,5H).

Preparation 116 2-(5-Aminopyridin-2-yl)ethan-1-ol

The title compound was prepared according to the method described forPreparation 40 using methyl 2-(5-aminopyridin-2-yl)acetate (PCTPublication No. WO2007042299).

¹H NMR (400 MHz, MeOH-d₄): δ ppm 2.80-2.85 (t, 2H), 3.80 (t, 2H), 7.05(m, 2H), 7.90 (s, 1H).

Preparation 117 Racemic-1-(5-Amino-3-chloropyridin-2-yl)ethan-1-ol

To a suspension of racemic-tert-butyl(5-chloro-6-(1-hydroxyethyl)pyridin-3-yl)carbamate_(Preparation 118, 2.2g, 8 mmol) in MeOH (50 mL) was added HCl/dioxane (4M, 30 mL) at 0° C.The reaction was stirred at room temperature for 18 hours beforeconcentrating in vacuo to afford the title compound as the hydrochloridesalt, which was taken on directly to the next step (2.2 g, 100%).

Preparation 118 Racemic-tert-Butyl(5-chloro-6-(1-hydroxyethyl)pyridin-3-yl)carbamate

To a suspension of di-tert-butyl(6-acetyl-5-chloropyridin-3-yl)carbamate (Preparation 119, 2.33 g, 6.7mmol) in MeOH (50 mL) was added sodium borohydride (656 mg, 17.25 mmol)at 0° C. The reaction was stirred at room temperature for 3 hours beforebeing quenched by the addition of water and extracted with EtOAc (3×50mL). The combined organic layers were concentrated in vacuo to affordthe title compound as a white solid (2 g, 85%). MS m/z 372 [M+H]⁺

Preparation 119 tert-Butyl (6-acetyl-5-chloropyridin-3-yl)carbamate

To a suspension of di-tert-butyl(5-chloro-6-(methoxy(methyl)carbamoyl)pyridin-3-yl)carbamate(Preparation 120, 2.1 g, 6.7 mmol) in THF (150 mL) was added MeMgCl (2.2mL, 3 mol/L) dropwise at −30° C. The reaction was stirred at roomtemperature for 3 hours before quenching with the addition of water. Thereaction was extracted into EtOAc (3×50 mL) and concentrated in vacuo toafford the title compound as a white solid (2.3 g, 77%). MS m/z 271[M+H]⁺

Preparation 120 Di-tert-Butyl(5-chloro-6-(methoxy(methyl)carbamoyl)pyridin-3-yl)carbamate

To a solution of methyl5-((di-tert-butoxycarbonyl)amino)-3-chloropicolinate (Preparation 121, 2g, 5.18 mmol) in THF/H₂O (100 mL/50 mL) was added LiOH (435 mg, 10.36mmol) at 0° C. and stirred at room temperature for 2 hours. The reactionwas adjusted pH=2 with citric acid and extracted with EtOAc (3×100 mL).The combined organic layers were dried over sodium sulfate andconcentrated in vacuo. The residue (1.35 g, 3.6 mmol) was dissolved inDCM (100 mL) and treated with N,O-dimethylhydroxylamine hydrochloride(423 mg, 4.3 mmol), triethylamine (1.1 g, 11 mmol) and HATU (1.65 g, 4.3mmol) at 0° C. The reaction was stirred at room temperature for 3 hours.The reaction was concentrated in vacuo and purified directly usingsilica gel column chromatography eluting with 30% EtOAc in petroleumether to afford the title compound (1.4 g, 94%). MS m/z 416 [M+H]⁺

Preparation 121 Methyl5-((di-tert-butoxycarbonyl)amino)-3-chloropicolinate

To a solution of methyl 5-amino-3-chloropicolinate (1.42 g, 7.63 mmol)and di-tert-butyldicarbonate (4.7 g, 18.8 mmol) in THE (150 mL) wasadded DIPEA (2.95 g, 22.87 mmol followed by DMAP (47 mg, 0.38 mmol). Thereaction was heated to 70° C. for 3 hours. The reaction was concentratedin vacuo and purified by silica gel column chromatography eluting with30% EtOAc in petroleum ether to afford the title compound (2.5 g, 85%).MS m/z 387 [M+H]⁺

Preparation 122 (5-Amino-3-chloropyridin-2-yl)methanol

The title compound was prepared according to the method described forPreparation 40 using methyl 5-amino-3-chloropicolinate. The residue waspurified using silica gel column chromatography eluting with 30%petroleum ether on EtOAc. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 4.42-4.44 (d,2H), 4.88 (t, 1H), 5.57 (br s, 2H), 6.97 (s, 1H), 7.83 (s, 1H).

Preparation 123 1-(Oxetan-3-yl)-1H-pyrazol-4-amine

To a solution of 4-nitro-1-(oxetan-3-yl)-1H-pyrazole (Preparation 124,119 mg, 0.70 mmol) in MeOH (20 mL) was added wet Pd/C (30 mg) and thereaction was hydrogenated under a balloon of hydrogen at roomtemperature for 2 hours. The reaction was filtered and the filtrateconcentrated in vacuo to afford the title compound (100 mg, 100%).

Preparation 124 4-Nitro-1-(oxetan-3-yl)-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (0.3 g, 2.66 mmol) and3-iodo-oxetane (1.47 g, 7.99 mmol) in DMF (13 mL) was added cesiumcarbonate (1.7 g, 5.23 mmol) and the reaction was heated to 100° C. for18 hours. The reaction was concentrated in vacuo and purified by silicagel column chromatography eluting with EtOAc to afford the titlecompound (380 mg, 86%).

¹H NMR (400 MHz, MeOH-d₄): δ ppm 5.02 (br s, 4H), 5.61 (br s, 1H), 8.24(br s, 1H), 8.68 (br s, 1H).

Preparation 125 4-Amino-6-(hydroxymethyl)-N-methylpicolinamide

Methyl 4-((tert-butoxycarbonyl)amino)-6-(hydroxymethyl)picoinate(Preparation 63, 220 mg, 0.78 mmol) in 2M methylamine in MeOH (4 mL) washeated to 60° C. for 18 hours. The reaction was cooled and the resultingsolid filtered, dried, and dissolved in DCM (4 mL). To the solution wasadded MeOH (1 mL) followed by 4M HCl in dioxane (3 mL) and the reactionwas stirred at room temperature for 4 hours. The resulting solid wasfiltered and dried to afford the title compound as the hydrochloridesalt (75 mg, 40% over 2 steps). LCMS Rt=0.16 minutes; MS m/z 182 [M+H]⁺

Preparation 1264-((4-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)-5-fluoropyrimidin-2-yl)amino)-N-ethyl-2-methylbenzamide

To a solution ofN-ethyl-4-((5-fluoro-4-(6-(2,2,2-trifluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrimidin-2-yl)amino)-2-methylbenzamide(Example 121, 100 mg, 0.21 mmol) in MeOH (5 mL) was added 1M NaOH (aq)(2 mL) and the reaction was stirred at 50° C. for 1 hour. The reactionwas concentrated in vacuo and partitioned between DCM and water. Theorganic phase was collected through a phase separation cartridge andconcentrated in vacuo to afford the title compound that was useddirectly in the next reaction.

Preparation 1274-((4-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)pyrimidin-2-yl)amino)-N-ethylbenzamidehydrochloride

To a solution of 4-((4-chloropyrimidin-2-yl)amino)-N-ethylbenzamide(Preparation 132, 1.2 g, 4.3 mmol) and tert-butyl3,6-diazabicyclo[3.1.1]heptanes-6-carboxylate (900 mg, 5 mmol) in THF(20 mL) was added triethylamine (2 mL, 10 mmol) and the reaction washeated to 50° C. for 18 hours. The reaction was cooled and purifieddirectly using silica gel column chromatography eluting with 0-20% MeOHin DCM. The residue was dissolved in 1:1 MeOH:DCM (10 mL) and treatedwith 4M HCl in dioxane (5 mL). The reaction was stirred at roomtemperature for 18 hours before concentrating in vacuo. The resultingsolid was collected as the hydrochloride salt of the title compound (1.5g, quant).

MS m/z 339 [M+H]⁺

Preparation 1284-((4-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)pyrimidin-2-yl)amino)-N-ethyl-2-methylbenzamidehydrochloride

To a solution of tert-butyl3-(2-chloropyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate(Preparation 131, 100 mg, 0.3 mmol) and4-amino-N-ethyl-2-methylbenzamide (PCT Publication No. WO2006109846, 60mg, 0.34 mmol) in dioxane (3 mL) was added sodium tert-butoxide (35 mg,0.36 mmol) and RuPHOS (25 mg, 0.034 mmol). The reaction was heated to140° C. under microwave irradiation for 25 minutes. The reaction wascooled, filtered and purified directly using silica gel columnchromatography eluting with 0-20% MeOH in DCM. The residue was dissolvedin DCM (5 mL) and treated with 4M HCl in dioxane with a few drops ofMeOH to enable a solution. The reaction was stirred at room temperaturefor 18 hours and concentrated in vacuo to afford the title compound asthe hydrochloride salt that was used directly in the next reaction.

Preparation 1291-(3-(2-Chloro-5-fluoropyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-2,2,2-trifluoroethan-1-one

To a solution of tert-butyl3-(2-chloro-5-fluoropyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate(Preparation 130, 200 mg, 0.61 mmol) in DCM (5 mL) was added 4M HCl indioxane (4 mL) and the reaction was stirred at room temperature toensure removal of the tert-butoxycarbonyl protecting group. The reactionwas concentrated in vacuo, dissolved in DCM (5 mL), treated with TFAA(0.1 mL) and stirred at room temperature for 18 hours. The reaction wasconcentrated in vacuo and the residue partitioned between DCM and water.The organic layer was collected through a phase separation cartridge andconcentrated in vacuo to afford the title compound that was takendirectly on to the next step. MS m/z 325 [M+H]⁺

Preparation 130 tert-Butyl3-(2-chloro-5-fluoropyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

To a solution of 5-fluoro-2,4-dichloropyrimidine (0.85 g, 5.1 mmol) inMeOH (15 mL) was added tert-butyl3,6-diazabicyclo[3.1.1]heptanes-6-carboxylate (1 g, 5 mmol) followed bytriethylamine (3 mL, 20 mmol) and the reaction was stirred at roomtemperature for 18 hours. The resulting precipitate was filtered, washedwith MeOH and dried to afford the title compound as a white solid (1.46g, 88%).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.28 (s, 9H), 1.48 (d, 1H), 2.48-2.53(m, 1H), 3.70 (br s, 2H), 4.03-4.19 (m, 4H), 8.88 (d, 1H). MS m/z 329[M+H]⁺

Preparation 131 tert-butyl3-(2-chloropyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

The title compound was prepared according to the method described forPreparation 130 using 2,4-dichloropyrimidine and tert-butyl3,6-diazabicyclo[3.1.1]heptanes-6-carboxylate. The residue was purifiedusing silica gel column chromatography eluting with 0-100% EtOAc inheptanes.

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.24 (s, 9H), 1.44 (d, 1H), 2.48-2.56(m, 1H), 3.42 (m, 2H), 3.83 (br s, 1H), 3.92-4.04 (m, 1H), 4.15 (d, 2H),6.70 (br d, 1H), 8.09 (d, 1H). MS m/z 311 [M+H]⁺

Preparation 132 4-((4-Chloropyrimidin-2-yl)amino)-N-ethylbenzamide

To a solution of 4-((4-chloropyrimidin-2-yl)amino)benzoic acid(Preparation 133, 1 g, 4 mmol) in DCM (20 mL) was added ethylamine (4.4mL, 8.81 mmol) followed by HATU (1.71 g, 4.4 mmol) and triethylamine(1.23 mL, 8.81 mmol). The reaction was stirred at room temperature for30 minutes before being poured into water. The organic layer wasseparated, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified using silica gel column chromatography eluting with0-100% EtOAc in heptanes to afford the title compound (1 g, 90%).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.05 (t, 3H), 3.20-3.30 (m, 2H), 7.00(m, 1H), 7.70 (m, 4H), 8.30 (t, 1H), 8.45 (s, 1H), 10.25 (br s, 1H). MSm/z 277 [M+H]⁺

Preparation 133 4-((4-Chloropyrimidin-2-yl)amino)benzoic acid

A mixture of 4-((4-hydroxypyrimidin-2-yl)amino)benzoic acid (Preparation134, 5 g, 21.6 mmol) and POCl₃ was heated to reflux for 6 hours and thencooled to room temperature and concentrated in vacuo. The residue waspoured into ice-water and the resulting solid was collected byfiltration and dried to afford the title compound that was taken ondirectly to the next step.

Preparation 134 4-((4-Hydroxypyrimidin-2-yl)amino)benzoic acid

To a solution of 4-hydroxy-2-methylthiopyrimidine (5 g, 35.17 mmol) indiethylene glycol dimethyl ether (20 mL) was added 4-aminobenzoic acid(5.79 g, 42.2 mmol) and the reaction was heated to reflux for 18 hours.The reaction was cooled to room temperature and the resulting solid wasfiltered, washed with ether and dried to afford the title compound (6.5g, 35.17 mmol). A sample was purified and analysed using preparativeHPLC as described for Example 116 (Method 1, 5% B to 100% B in 9 min,hold at 100% B to 10 min) to obtain the following data. The remainderwas taken directly on to the next step. LCMS Rt=1.37 minutes; MS m/z 232[M+H]⁺

Preparation 1352-(3-((1R,5S)-3-(2-((1-Methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)azetidin-3-yl)acetonitrilehydrochloride

To a solution of 1-Boc-3-(cyanomethylene)azetidine (PCT Publication No.WO2013043964, 60 mg, 0.308 mmol) and4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19, 83 mg, 0.257 mol) in MeCN (1 mL) and EtOH(1 mL) was added DBU (77 μl, 0.514 mmol) and the reaction was heated to90° C. for 24 hours. Further4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19, 3 eq) was added and the reactioncontinued heating at 90° C. for 72 hours. The reaction was cooled,concentrated in vacuo and purified using silica gel columnchromatography eluting with 0-10% MeOH (with 1% ammonia). The residuewas dissolved in DCM (1 mL) and treated with 4M HCl in dioxane (1 mL).The reaction was stirred at room temperature for 1 hour beforeconcentrating in vacuo to afford the title compound as the hydrochloridesalt.

LCMS Rt=0.38 minutes; MS m/z 380 [M+H]⁺

Preparation 136 Ethyl2-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)oxazole-5-carboxylate

A mixture of4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-aminehydrochloride (Preparation 19, 300 mg, 0.614 mmol),ethyl-2-chloro-1,3-oxazole-5-carboxylate (300 mg, 1.71 mmol), potassiumphosphate (163 mg, 0.613 mmol), X-phos (60 mg, 0.126 mmol) and Pd₂(dba)₃(60 mg, 0.065 mmol) in DMSO (20 mL) was purged with nitrogen for 1minutes. The reaction was heated to 130° C. for 30 minutes undermicrowave irradiation. The reaction was filtered, concentrated in vacuoand purified by silica gel column chromatography 0-20% MeOH in DCM toafford the title compound (200 mg, 76%). MS m/z 425 [M+H]⁺

Preparation 137 and 138 tert-Butyl((1S,5R,6R)-3-(2-((5-chloro-6-((R)-1-hydroxyethyl)pyridin-3-yl)amino)-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamateand tert-Butyl((1S,5R,6R)-3-(2-((5-chloro-6-((S)-1-hydroxyethyl)pyridin-3-yl)amino)-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate

To a solution of racemic-1-(5-amino-3-chloropyridin-2-yl)ethan-1-ol(Preparation 117, 100 mg, 0.58 mmol), tert-butyl((1S,5R,6R)-3-(2-chloro-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate(Preparation 94, 187 mg, 0.46 mmol) and Cs₂CO₃ (375 mg, 1.16 mmol) inDMA (5 mL) was added Pd(OAc)₂ (25 mg, 0.93 mmol) and xantphos (65 mg,0.93 mmol) under nitrogen. The reaction was heated to 110° C. undermicrowave irradiation for 1 hour. The reaction was concentrated in vacuoand purified directly using silica gel column chromatography elutingwith 50% EtOAc in petroleum ether followed by preparative HPLC to affordthe racemic title compound. The racemate was separated into itsenantiomers by preparative chiral chromatography as described below:

Column: Chiralpak AS-3 150×4.6 mm I.D. 3 μm

Mobile phase: Ethanol (0.05% DEA) in CO₂ from 5% to 40%; Flow rate: 2.5mL/min

First Eluting Enantiomer:

Example 137: tert-Butyl((1S,5R,6R)-3-(2-((5-chloro-6-((R)-1-hydroxyethyl)pyridin-3-yl)amino)-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate.¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.88-0.90 (m, 3H), 1.20-1.30 (m, 1H),1.40 (m, 12H), 1.75 (m, 1H), 3.60 (m, 2H), 3.90 (m, 2H), 5.00 (m, 2H),7.55 (br s, 1H), 8.00 (m, 1H), 8.35 (br s, 1H), 8.75 (br s, 1H), 9.55(s, 1H). MS m/z 479 [M+H]⁺; 100% ee.

Second Eluting Isomer:

Example 138: tert-Butyl((1S,5R,6R)-3-(2-((5-chloro-6-((S)-1-hydroxyethyl)pyridin-3-yl)amino)-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate.¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.88-0.90 (m, 3H), 1.20-1.30 (m, 1H),1.35-1.39 (m, 12H), 1.75 (m, 1H), 3.60 (m, 2H), 3.90 (m, 2H), 5.00 (m,2H), 7.55 (br s, 1H), 8.00 (m, 1H), 8.38 (br s, 1H), 8.71 (br s, 1H),9.57 (s, 1H). MS m/z 479 [M+H]⁺; 100% ee.

Preparation 139 tert-butyl (6-chloro-5-fluoropyridin-3-yl)carbamate

To a solution of 5-bromo-2-chloro-3-fluoropyridine (62.5 g, 297 mmol×4),Xantphos (38.4 g, 327.8 mmol×4), and Cs₂CO₃ (6.87 g, 11.9 mmol×4) indioxane (2 L×4) was added Pd₂(dpa)₃ (10.8 g, 11.9 mmol×4). The mixturewas heated to 85° C. overnight. The reactions were combined thanfiltered. The filtrate was purified by silica gel column chromatographyeluting with 5% EtOAc in petroleum ether to afford the title compound(170 g, 58%). ¹H NMR (400 MHz, CDCl₃): δ ppm 1.53 (s, 9H), 6.78 (br. s.,1H), 7.99 (d, 1H), 8.05 (d, 1H)

Preparation 140 Methyl 5-((tert-butoxycarbonyl)amino)-3-fluoropicolinate

To a solution of tert-butyl (6-chloro-5-fluoropyridin-3-yl)carbamate(Preparation 139, 43.3 g, 175.67 mmol×3), DPPP (14.46 g, 35.1 mmol×3),TEA (124.1 g, 1.228 mol×3) in MeOH (600 mL×3) was added Pd(OAc)₂ (7.88g, 35.1 mmol×3). The mixture was stirred at 50 psi of CO at 60° C. for36 hrs. The reaction mixtures were combined, filtered and the filtratedwas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography eluting with 10% EtOAc in petroleumether to afford the title compound (33.7 g, 71%). ¹H NMR (400 MHz,CDCl₃): δ ppm 1.53 (s, 9H) 3.99 (s, 3H) 7.06 (br. s., 1H) 8.13 (d, 1H)8.24 (s, 1H)

Preparation 141 6-chloro-5-fluoropyridin-3-amine hydrochloride

A mixture of methyl 5-((tert-butoxycarbonyl)amino)-3-fluoropicolinate(Preparation 140, 1.50 g, 5.55 mmol) in 1 N HCl/dioxane (70 mL, 4 M) wasstirred at room temperature (10° C.) for 16 hours. The mixture wasconcentrated in vacuo to afford the title compound (1.1 g, 100%), whichwas used in the next step without further purification.

Preparation 142tert-butyl-3-(2-((5-fluoro-6-(methoxycarbonyl)pyridin-3-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

To a mixture of 6-chloro-5-fluoropyridin-3-amine hydrochloride(Preparation 141, 500 mg, 1.54 mmol), tert-butyl(1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(Preparation 34, 314 mg, 1.85 mmol) and Cs₂CO₃ (1000 mg, 3.08 mmol) inDMA (15 mL) was added Xantphos (178 mg, 0.308 mmol) and Pd(OAc)₂ (69.1mg, 0.308 mmol) at room temperature (10° C.). The mixture was bubbledwith N₂ for 3 min. The vial was sealed and then treated with microwaveirradiation at 120° C. for 1 h. The mixture was concentrated andpurified by column chromatography on silica gel 25% EtOAc in petroleumether to 75% EtOAc in petroleum ether to give the title compound (296mg, 42%). LCMS Rt=0.70 minutes; MS m/z 459 [M+H]

Preparation 143tert-butyl-3-(2-((6-carbamoyl-5-fluoropyridin-3-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A solution oftert-butyl-3-(2-((5-fluoro-6-(methoxycarbonyl)pyridin-3-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(Preparation 142, 400 mg, 0.11 mmol) in NH₃/MeOH (80 mL, 4 M) wasstirred at 100° C. in a 100 mL sealed tube for 8 h. The solution wasconcentrated in vacuo to afford the title compound (270 mg, 72%), whichwas used in the next step without further purification. LCMS Rt=0.67minutes; MS m/z 444 [M+H]

Preparation 1445-((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-3-fluoropicolinamidehydrochloride

To a mixture of Preparation 143 (250 mg, 0.564 mmol) in THE (10 mL) wasadded HCl/dioxane (20 mL, 4 M) at 0° C. The mixture was stirred at roomtemperature (10° C.) for 3 h. TLC (DCM:MeOH=10:1) showed some of thestarting material was still remained. The solution was concentrated invacuo to afford the title compound (300 mg, yield: 100%), which wastaken to the next step directly.

Biological Evaluation

Compounds of the invention were evaluated by in vitro methods todetermine their respective ability to inhibit the JAK kinases (TYK2,JAK1, JAK2, JAK3).

Assay Format

The human JAK inhibitory activity was determined by using a microfluidicassay to monitor phosphorylation of a synthetic peptide by therecombinant human kinase domain of each of the four members of the JAKfamily, JAK1, JAK2, JAK3 and TYK2. Reaction mixtures contained 1 M of afluorescently labeled synthetic peptide, a concentration less than theapparent K_(m), and 1 mM ATP. Each assay condition was optimized forenzyme concentration and room temperature incubation time to obtain aconversion rate of 20% to 30% phosphorylated peptide product. Reactionswere terminated by the addition of stop buffer containing EDTA.Utilizing the LabChip 3000 mobility shift technology (Caliper LifeScience), each assay reaction was sampled to determine the level ofphosphorylation. This technology is separation-based, allowing directdetection of fluorescently labeled substrates and products. Separationsare controlled by a combination of vacuum pressure and electric fieldstrength optimized for each peptide substrate.

Assay Protocol

JAK Caliper Enzyme Assay at 1 mM ATP

Compounds were added to a 384-well plate. Reaction mixtures contained 10mM HEPES, pH 7.4, 10 mM MgCl₂, 0.01% BSA, 0.0005% Tween 20, 1 mM ATP and1 M peptide substrate. The JAK and TYK2 assays contained 1 M of theIRStide peptide (5FAM-KKSRGDYMTMQID) and the JAK2 and JAK3 assayscontained 1 M of the JAKtide peptide (FITC-KGGEEEEYFELVKK). The assayswere initiated by the addition of 20 nM JAK1, 1 nM JAK2, 1 nM JAK or 1nM TYK2 enzyme and were incubated at room temperature for three hoursfor JAK1, 60 minutes for JAK2, 75 minutes for JAK3 or 135 minutes forTYK2. Enzyme concentrations and incubation times were optimized for eachnew enzyme preps and were modified slightly overtime to ensure 20% to30% phosphorylation. The assays were stopped with 15 μL of 180 mM HEPES,pH 7.4, 20 mM EDTA, and 0.2% Coating Reagent 3. The assay plates wereplaced on a Caliper Life Science LC3000 instrument, and each well wassampled using appropriate separation conditions to measure theunphosphorylated and phosphorylated peptide.

Data Analysis

The data was collected using the HTS Well Analyzer software from CaliperLife Sciences. The data output for data analysis is the percent productconverted calculated on peak height (Equation 1).% product converted=100*((product)/(product+substrate))  Equation 1:

The percent effect at each compound concentration was calculated basedon the positive and negative control well contained within each assayplate (Equation 2). The positive control wells contained a saturatingconcentration of a control compound that produced a level ofphosphorylation comparable to background (i.e., completely inhibitedJAK1, JAK2, JAK3 or TYK2). The negative control wells contained DMSOalone (at the same concentration as the compound wells) that was used toset the baseline activity in the assay (i.e., uninhibited JAK1, JAK2,JAK3 or TYK2).% effect=100*((sample well−negative control)/(positive control−negativecontrol))  Equation 2:

The percent effect was plotted against the compound concentrationcompound. An unconstrained sigmoid curve was fitted using a 4 parameterlogistic model and the compound concentration required for 50%inhibition (IC₅₀) was determined (Equation 3).y=((max−min)/(1+((x/IC ₅₀){circumflex over ( )}s)))+min  Equation 3:

Where max is the maximum asymptote (complete inhibition), min is theminimum asymptote (no inhibition) and s is the slope factor. IC₅₀ valuesare reported in nM for each compound:

Ex. IC₅₀ (nM) No. Structure TYK2 JAK1 JAK2 JAK3 1

1098 2730 >10000 >10000 2

432 1547 4721 >10000 3

128 215 1974 >10000 4

176 659 2885 >10000 5

41 41 477 >10000 6

36 337 754 >10000 7

23 17 77 6494 8

702 842 3148 >10000 9

4 20 112 1661 10

22 171 367 >10000 11

40 139 141 >10000 12

28 79 80 >10000 13

12 41 199 >10000 14

79 757 745 >10000 15

84 588 855 >10000 16

66 150 421 >10000 17

242 684 3375 >10000 18

62 352 331 >10000 19

52 463 402 >10000 20

58 314 346 >10000 21

95 622 434 >10000 22

55 490 312 >10000 23

58 258 498 >10000 24

32 13 67 4987 25

34 317 468 >10000 26

25 60 192 >10000 27

61 78 640 >10000 28

736 1371 8152 >10000 29

31 131 487 >10000 30

97 1156 2126 >10000 31

32 78 401 >10000 32

17 28 140 >10000 33

15 62 116 9276 34

36 152 377 >10000 35

23 170 337 >10000 36

76 199 684 >10000 37

250 467 1398 8306 38

427 707 2328 >10000 39

136 305 1171 >10000 40

70 369 189 >10000 41

84 201 279 >10000 42

437 717 2459 >10000 43

474 902 2842 >10000 44

72 475 854 >10000 45

17 46 100 7402 46

84 173 526 4158 47

65 42 262 >10000 48

964 300 2508 >10000 49

49 77 614 >10000 50

436 478 3418 >10000 51

11 13 97 8611 52

93 172 1241 >10000 53

24 226 375 >10000 54

8 19 29 4292 55

23 35 221 8615 56

41 110 394 >10000 57

89 294 1069 >10000 58

73 267 821 >10000 59

62 78 236 8798 60

70 36 159 >10000 61

18 31 44 4083 62

224 1021 1387 >10000 63

125 303 856 >10000 64

41 95 320 >10000 65

22 35 223 >10000 66

65 106 655 >10000 67

108 418 973 >10000 68

22 85 188 >10000 69

811 1098 5703 >10000 70

261 259 1541 >10000 71

152 153 453 >10000 72

6 81 151 411 73

17 260 170 1771 74

65 67 691 >10000 75

66 462 1289 >10000 76

662 537 1476 >10000 77

256 380 653 >10000 78

63 68 461 >10000 79

34 38 406 8425 80

79 190 436 >10000 81

199 405 603 >10000 82

79 135 473 >10000 83

11 7 21 1239 84

62 141 155 >10000 85

16 13 67 2477 86

71 104 538 >10000 87

93 337 1787 >10000 88

110 165 894 >10000 89

9 10 65 4426 90

14 17 76 4168 91

39 183 513 >10000 92

62 52 264 6564 93

28 41 652 4267 94

56 113 1132 4023 95

35 11 228 255 96

924 684 2676 >10000 97

588 672 1883 9970 98

19 13 147 2599 99

26 65 391 4937 100

97 965 4253 >10000 101

663 1881 2908 >10000 102

252 2076 6872 >10000 103

150 1738 3465 >10000 104

86 1150 3127 >10000 105

152 1569 6100 >10000 106

229 2297 9412 >10000 107

21 19 177 1883 108

675 323 1491 3964 109

51 211 2337 >10000 110

58 29 455 928 111

56 1691 2214 4867 112

21 4068 3037 >10000 113

82 8584 7865 >10000 114

62 955 1855 >10000 115

64 3790 3309 >10000 116

20 1469 1911 9819 117

32 114 452 >100002. Selected compounds were assessed for their ability to inhibitinterferon alpha signalling in a human whole blood flow cytometry assay.Intereron alpha signals through TYK2 and JAK1.Human Whole Blood INFα Induced STAT3 Phosphorylation Assay

Test articles were prepared as 30 mM stocks in DMSO. A 11-point 2.5dilution series was created in DMSO with a top concentration of 5 mM.Further dilution was done by adding 4 μL of the above test articlesolutions into 96 μL of PBS with a top concentration of 200 μM. Humanwhole blood was collected from healthy donors via vein puncture intoVacutainer collection tubes containing sodium heparin (Catalog No.366480; Becton Dickinson, Franklin Lakes, N.J.). Blood was warmed to 37°C. prior to use. Human whole blood was aliquoted (90 μL/well) in96-well, deep-well, V-bottom plates and treated with compounds at 11different concentrations (0.2% DMSO final) at 37° C. for 60 minutes.This was followed by a challenge with IFNα (5 μL/well; final, 5000 U/MI)for 15 minutes. Samples were treated with warm 1× Lyse/Fix buffer (700μL/well) to terminate activation and further incubated at 37° C. for 20minutes to lyse red blood cells. Plates were centrifuged at 300×g for 5minutes, supernatant was aspirated, and cells were washed with 800 μLper well of staining buffer. The washed cell pellets were resuspendedwith 350 μL per well of pre-chilled 90% methanol, and incubated on icefor 30 minutes. After the removal of 90% methanol, cells were washedonce with staining buffer (800 μL/well). Cell pellets were resuspendedin staining buffer containing anti-pSTAT3-AlexaFluor647 (1 to 150dilution, 150 μL/well), and incubated at room temperature in the darkovernight.

Samples were transferred to 96-well U-bottom plates and flow cytometricanalysis was performed on a FACSCalibur, FACSCanto or LSRFortessaequipped with a HTS plate loader (BD Biosciences). The lymphocytepopulation was gated for histogram analysis of pSTAT3. Backgroundfluorescence was defined using unstimulated cells and a gate was placedat the foot of the peak to include ˜0.5% gated population. The histogramstatistical analysis was performed using CellQuest™ Pro version 5.2.1(BD Biosciences), FACSDiva version 6.2 (BD Biosciences) or FlowJoversion 7.6.1 (Ashland, Oreg.) software. Relative fluorescence unit(RFU), which measures the level of phospho STAT3, was calculated bymultiplying the percent positive population and its mean fluorescence.Data from 11 compound concentrations (singlicate at each concentration)was normalized as a percentage of control based on the formula: % ofControl=100×(A−B)/(C−B)

where A is the RFU from wells containing compound and cytokine, B is theRFU from wells without cytokine and compound (minimum fluorescence) andC is the RFU from wells containing only cytokine (maximum fluorescence).Inhibition curves and IC50 values were determined using the Prismversion 5 software (GraphPad, La Jolla, Calif.).

Example Number HWB IFN alpha IC50 (nM) 5 105 6 232 7 30 10 439 11 134 1288 14 287 15 534 18 338 19 238 20 458 21 731 22 410 23 428 24 43 25 22926 247 27 139 29 118 30 653 31 284 32 115 33 122 35 90 36 119 44 562 45110 46 209 49 85 51 20 53 287 55 168 56 78 57 338 58 158 59 84 60 103 61135 64 71 65 60 66 187 74 213 75 751 79 65 80 112 83 85 84 156 85 120 86116 87 582 89 118 90 247 91 195 93 191 95 87 98 246 109 507 110 146 112775 113 939 114 166 115 234

What is claimed is:
 1. A compound having the structure:

or a pharmaceutically acceptable salt thereof, wherein X is N; A isselected from the group consisting of a bond and C═O; R₁ is C₃-C₆cycloalkyl, wherein said cycloalkyl is further optionally substitutedwith one or more halo; R₂ is hydrogen; R₃ is hydrogen; R₄ is monocyclicheteroaryl wherein said heteroaryl is optionally substituted with one ormore C₁-C₆ alkyl; and, R₅ is hydrogen; and, j is 0 or1.
 2. The compoundof claim 1, wherein A is C═O, or a pharmaceutically acceptable saltthereof.
 3. The compound of claim 1, wherein j is 0, or apharmaceutically acceptable salt thereof.
 4. The compound of claim 1,wherein R₄ is monocyclic heteroaryl and said monocyclic heteroaryl ispyrazole, or a pharmaceutically acceptable salt thereof.
 5. The compoundof claim 4, wherein said monocyclic heteroaryl is pyrazole substitutedby C₁-C₆ alkyl, or a pharmaceutically acceptable salt thereof.
 6. Acompound having the structure:

or a pharmaceutically acceptable salt thereof, wherein R₁ is C₃-C₆cycloalkyl, further optionally substituted with one or more halo andwherein R′ is C₁-C₆ alkyl.
 7. The compound of claim 6 having thestructure:

wherein R′ is C₁-C₆ alkyl.
 8. The compound of claim 6 having thestructure:

wherein R′ is C₁-C₆ alkyl.
 9. A pharmaceutical composition comprising acompound of any of claims 1 to 8, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.